YAP1 in control: how RNA networks and protein modifications shape its function and therapeutic targetability.

The biological activity of YAP1 is tightly controlled by an interconnected network of post-translational modifications (PTMs) that collectively govern protein stability, subcellular trafficking, and transcriptional output through antagonistic, cooperative, and sequential regulatory interactions (Fig.  4 ). Among these modifications, phosphorylation serves as a major regulatory node, frequently influencing additional PTMs by inducing conformational shifts or generating signals for protein turnover. In pancreatic cancer, SDCBP suppresses CK1δ/ε-mediated phosphorylation of YAP1 at S384/S387, thereby preventing β-TrCP-dependent ubiquitination and degradation and markedly increasing YAP1 abundance in both cytoplasmic and nuclear compartments, ultimately enhancing cancer cell proliferation and metastatic potential [ 20 ]. In glioblastoma, FRK phosphorylates YAP1 at Tyr391/407/444, promoting recruitment of the E3 ubiquitin ligase Siah1, triggering ubiquitination and proteasomal degradation of YAP1, and restricting tumor progression [ 56 ]. In colorectal cancer, lncRNA SNHG29 inhibits YAP1 phosphorylation at S127, reducing ubiquitination and contributing to immune evasion [ 57 ]. In melanoma and breast cancer, MAP3K3-mediated phosphorylation of YAP1 at S405 interferes with FBXW7-dependent ubiquitination and lysosomal degradation [ 58 ], whereas in nasopharyngeal carcinoma, circTP63-N enhances LATS-driven phosphorylation of YAP1 at S127, promoting ubiquitination and degradation and thereby limiting cancer cell proliferation and metastasis [ 59 ]. Fig. 4 Dynamic interplay of post-translational modifications and regulatory network of YAP1 protein stability. YAP1 stability, subcellular distribution, and transcriptional activity are coordinately controlled through interactions among phosphorylation, ubiquitination, acetylation, SUMOylation, and O-GlcNAcylation in conjunction with Hippo pathway signaling, thereby influencing proliferation, migration, invasion, and tumorigenesis. Key crosstalk mechanisms include the following: at the phosphorylation–ubiquitination interface, SDCBP competitively associates with YAP1, disrupting CK1–YAP1 interaction, inhibiting YAP1 phosphorylation, and preventing β-TrCP binding to phosphorylated YAP1, ultimately reducing ubiquitination and increasing YAP1 protein abundance. At the ubiquitination–acetylation level, PXR interacts with YAP1 and promotes Sirt2-mediated deacetylation, suppressing K48-linked degradative ubiquitination while enhancing K63-linked stabilizing polyubiquitination, thereby strengthening YAP1–TEAD nuclear association. At the phosphorylation–SUMOylation level, CBX4 binds YAP1 and mediates SUMOylation at K97/K280, which competitively inhibits LATS-dependent phosphorylation and promotes nuclear localization. At the ubiquitination–SUMOylation interface, elevated SENP3 catalyzes YAP1 deSUMOylation, facilitating ubiquitin-dependent degradation. At the phosphorylation–O-GlcNAcylation level, UDP-GlcNAc–activated OGT associates with YAP1 and catalyzes O-GlcNAcylation at Thr241, thereby antagonizing LATS1-mediated phosphorylation and enhancing nuclear accumulation. At the ubiquitination–O-GlcNAcylation level, OGT-mediated O-GlcNAcylation at Thr83 promotes recruitment of the deubiquitinase EIF3H to glycosylated YAP1, resulting in removal of ubiquitin chains and stabilization of the YAP1 protein. Created by Figdraw Dynamic interplay of post-translational modifications and regulatory network of YAP1 protein stability. YAP1 stability, subcellular distribution, and transcriptional activity are coordinately controlled through interactions among phosphorylation, ubiquitination, acetylation, SUMOylation, and O-GlcNAcylation in conjunction with Hippo pathway signaling, thereby influencing proliferation, migration, invasion, and tumorigenesis. Key crosstalk mechanisms include the following: at the phosphorylation–ubiquitination interface, SDCBP competitively associates with YAP1, disrupting CK1–YAP1 interaction, inhibiting YAP1 phosphorylation, and preventing β-TrCP binding to phosphorylated YAP1, ultimately reducing ubiquitination and increasing YAP1 protein abundance. At the ubiquitination–acetylation level, PXR interacts with YAP1 and promotes Sirt2-mediated deacetylation, suppressing K48-linked degradative ubiquitination while enhancing K63-linked stabilizing polyubiquitination, thereby strengthening YAP1–TEAD nuclear association. At the phosphorylation–SUMOylation level, CBX4 binds YAP1 and mediates SUMOylation at K97/K280, which competitively inhibits LATS-dependent phosphorylation and promotes nuclear localization. At the ubiquitination–SUMOylation interface, elevated SENP3 catalyzes YAP1 deSUMOylation, facilitating ubiquitin-dependent degradation. At the phosphorylation–O-GlcNAcylation level, UDP-GlcNAc–activated OGT associates with YAP1 and catalyzes O-GlcNAcylation at Thr241, thereby antagonizing LATS1-mediated phosphorylation and enhancing nuclear accumulation. At the ubiquitination–O-GlcNAcylation level, OGT-mediated O-GlcNAcylation at Thr83 promotes recruitment of the deubiquitinase EIF3H to glycosylated YAP1, resulting in removal of ubiquitin chains and stabilization of the YAP1 protein. Created by Figdraw Competitive interplay between phosphorylation and other modifications constitutes an additional regulatory mechanism (Fig.  4 ). In gastric cancer, CBX4-catalyzed SUMOylation of YAP1 directly inhibits phosphorylation at S127, promoting nuclear localization and contributing to chemotherapy resistance [ 60 ]. Conversely, PKCα-driven phosphorylation promotes subsequent SUMOylation of YAP1, redirecting signaling from pro-proliferative TEAD-dependent transcription toward pro-apoptotic p73-associated programs and thereby restraining malignant phenotypes [ 61 ]. Similarly, O-GlcNAcylation of YAP1 at Thr383 [ 62 ], Ser109 [ 63 ], or Thr241 [ 64 ] interferes with LATS1/2-mediated phosphorylation and degradation, enhancing nuclear accumulation and induction of pro-tumorigenic and angiogenic gene expression. Reciprocal switching between ubiquitination and other PTMs further broadens regulatory complexity (Fig.  4 ). In liver regeneration models, PXR activation induces Sirt2-dependent deacetylation of YAP1, suppressing degradative K48-linked ubiquitination while promoting stabilizing K63-linked polyubiquitination. This shift strengthens nuclear retention of YAP1 and its association with TEAD, thereby stimulating hepatocyte proliferation and regenerative responses [ 65 ]. In triple-negative breast cancer, elevated SENP3 promotes deSUMOylation of YAP1, enhancing ubiquitination-dependent degradation and ultimately reducing migration, invasion, and stemness [ 66 ]. PTM networks also intersect with metabolic signaling. In obesity-associated triple-negative breast cancer, adipocyte-derived O-GlcNAcylation at Thr83 recruits the deubiquitinase EIF3H to stabilize YAP1, driving tumor progression and chemoresistance, whereas the anti-obesity agent retatrutide restores chemotherapy responsiveness by disrupting this glycosylation–deubiquitination axis [ 67 ].

YAP1 serves as a central regulator of cellular senescence through coordinated post-translational modifications, modulation of signaling cascades, and integration of microenvironmental cues. A multidimensional mechanistic framework for therapeutic targeting of YAP1 in senescence-associated disorders is thereby provided (Fig.  5 ). In gastric cancer, the SUMO E3 ligase CBX4 mediates SUMO1 conjugation of YAP1 at lysine residues K97 and K280. This modification competitively impedes phosphorylation at Ser127, limiting cytoplasmic retention and degradation. Enhanced nuclear accumulation of YAP1 subsequently suppresses p53- and p21-dependent senescence pathways, counteracting cellular senescence and promoting chemotherapy resistance [ 60 ]. In idiopathic pulmonary fibrosis, the anti-aging molecule NPNT interacts with integrin ITGA3, attenuating activation of upstream Hippo kinases LATS1/MOB1. Reduced YAP1 phosphorylation and ubiquitin-mediated degradation promote nuclear enrichment and inhibit senescence of alveolar epithelial cells [ 78 ]. Activation of MST kinases by FRMD6 increases YAP1 phosphorylation and degradation, leading to reduced expression of the YAP1 target gene CCN3 and induction of cellular senescence. Upregulation of FRMD6 by TGF-β through the p53/SMAD pathway establishes a positive feedback circuit that reinforces the SASP [ 79 ]. YAP1 also represses transcription of the Rho family GTPase RHOU, modulating actin cytoskeletal dynamics and cellular enlargement. This mechanism antagonizes nuclear localization of GATA4/NF-κB and limits the SASP. Diminished YAP1 activity intensifies the SASP without altering growth arrest [ 80 ]. In models of hepatic inflammation, reduced YAP1 expression in aged mesenchymal stem cells (MSCs) decreases STAT1 and iNOS levels, weakening the immunosuppressive effects of MSCs on CD8 + T cells and aggravating inflammatory responses. Restoration of YAP1 expression partially corrects this immune dysregulation [ 81 ]. During gingival aging, progressive reduction in nuclear YAP1 impairs proliferation of gingival epithelial cells, disrupts epithelial barrier integrity, and enhances inflammatory responses. YAP1 knockdown recapitulates senescent phenotypes, whereas enforced expression restores regenerative capacity in aged gingival tissue [ 82 ].

The post-transcriptional and post-translational regulatory network governing YAP1 functions as a central signaling hub across multiple pathological conditions, providing numerous candidates for precision intervention while simultaneously introducing substantial complexity. Recent preclinical investigations have demonstrated encouraging activity for agents that directly inhibit YAP1, modulate non-coding RNAs, or interfere with specific post-translational modifications. Identification of multifunctional compounds such as Verteporfin further illustrates the feasibility of drug repurposing strategies. Nevertheless, clinical translation remains constrained by extensive regulatory crosstalk and context-dependent effects within YAP1 signaling. For example, competitive SUMOylation and phosphorylation of YAP1 can promote chemotherapy resistance in gastric cancer, whereas acetylation may exert divergent tumor-promoting or tumor-restraining effects depending on the microenvironmental context. Future efforts should emphasize development of highly selective therapeutics directed at specific YAP1 isoforms or defined post-translational modifications. Approaches such as PROTACs, which recruit E3 ubiquitin ligases to trigger YAP1 ubiquitination, may enable more efficient and selective protein degradation [ 147 ]. Nanoparticle-based delivery platforms offer potential solutions to in vivo instability of RNA-based therapeutics and may enhance therapeutic index while reducing off-target toxicity [ 148 ]. Rational optimization of combination regimens also warrants attention; integration of YAP–TEAD inhibitors with immune checkpoint blockade, for instance, may improve treatment efficacy through modulation of the immunosuppressive microenvironment [ 149 ]. Interpatient heterogeneity presents an additional barrier to effective clinical application. Integration of single-cell sequencing with PDO models may delineate intratumoral diversity in YAP1 signaling and inform individualized therapeutic strategies [ 150 ]. CRISPR/Cas9-based epigenetic editing technologies provide precise control of non-coding RNA expression or YAP1 activity without altering genomic sequences, offering a platform for targeted functional modulation [ 151 ]. Emerging insights into YAP1 transcriptional regulation provide important directions for future investigation. Recent evidence indicates that YAP1 governs stem cell proliferation, developmental homeostasis, and tumorigenesis through induction of hypertranscription. Dosage-dependent control of hypertranscription by YAP1 has been validated as a mechanism balancing neural progenitor cell numbers during neural development [ 152 ], and this phenomenon is evolutionarily conserved in embryonic stem cells and adult tissue stem cells. Accurate detection of hypertranscription requires specialized analytical approaches, including cell-number–normalized strategies, to avoid distortion associated with conventional read-depth normalization [ 153 ]. The precise number of direct YAP1 target genes remains debated due to variability in detection platforms, cellular models, and validation standards. Functional diversity among YAP1 target genes appears to reflect conservation of essential core targets alongside cell type–specific auxiliary targets. Moreover, YAP1-driven release of paused RNA polymerase II through recruitment of the mediator complex and CDK9 kinase has been identified as a distinct transcriptional mechanism, providing additional molecular candidates for therapeutic targeting [ 154 ]. Further investigation is required to delineate the intricate regulatory structure governing YAP1 post-transcriptional and post-translational modifications and to clarify how modifications such as phosphorylation and SUMOylation, together with RNA-level regulation, influence hypertranscriptional capacity and target gene selectivity. Integration of single-cell multi-omics with functional validation platforms will be necessary to define core YAP1 target networks and to characterize signaling crosstalk that may reveal additional therapeutic entry points. Building on these advances, development of highly selective and potent agents targeting YAP1 regulatory circuits, refinement of drug design and delivery technologies, and expansion of translational clinical studies will establish a more robust framework for precision YAP1-directed therapy and promote its application in cancer, cardiovascular disease, fibrosis, and related disorders.

Non-coding RNAs (ncRNAs) constitute a complex regulatory network that dynamically modulates the stability and translational efficiency of YAP1 mRNA through ceRNA interactions and direct miRNA-mediated targeting. Long noncoding RNAs (lncRNAs) act as molecular sponges that sequester specific miRNAs, thereby forming a central regulatory axis within the Hippo/YAP1 signaling pathway and influencing tumorigenesis as well as cardiovascular pathology. In multiple malignancies, distinct lncRNAs relieve repression of YAP1 or its key upstream regulators by tumor-suppressive miRNAs, thereby enhancing oncogenic signaling (Fig.  1 ). In cholangiocarcinoma, YY1-induced lncRNA DLEU1 and m6A-modified lncRNA NKILA upregulate YAP1 expression through sequestration of miR-149-5p and miR-582-3p, respectively, promoting proliferation, invasion, and stemness [ 22 , 23 ]. In pancreatic cancer, lncRNA THAP9-AS1 exerts dual regulatory functions: it sequesters miR-484 to increase YAP1 expression and directly associates with the YAP1 protein to inhibit its inactivating phosphorylation, thereby establishing a feed-forward circuit with the YAP1/TEAD complex that supports tumor progression [ 24 ]. In gastric cancer, linc01133 sponges miR-145-5p, attenuates suppression of YES1, and enhances YAP1 nuclear translocation and cell cycle progression [ 25 ]. CFIm25-regulated lncRNA acv3UTR enhances the oncogenic activity of YAP1 through sequestration of miR-590-5p [ 26 ]. In cardiac tissue, lncExACT1 promotes pathological hypertrophy by modulating microRNA-222, calcineurin signaling, and Hippo/YAP1 signaling via DCHS2 [ 27 ]. Conversely, in breast cancer, lncRNA MIR22HG functions as a tumor suppressor by sponging miR-629-5p, stabilizing LATS2 mRNA, and enhancing LATS2-dependent phosphorylation and inactivation of YAP1 [ 28 ]. In chemotherapy-induced premature ovarian failure, extracellular vesicles derived from hUCMSC deliver lncRNA HCP5, which sequesters miR-20a-5p, thereby reversing miR-20a-5p-mediated post-transcriptional repression of YAP1 and increasing YAP1 expression. As a result, granulosa cell proliferation is restored, apoptosis is reduced, DNA damage repair is enhanced, and disease progression is attenuated [ 29 ]. In chronic periodontitis, downregulation of lncRNA EPB41L4A-AS1 disrupts its function as a ceRNA targeting miR-214-3p; restoration of EPB41L4A-AS1 relieves miR-214-3p-mediated suppression of YAP1. This regulatory axis preserves periodontal ligament cell viability, limits excessive inflammatory responses, promotes osteogenic differentiation, and delays disease progression [ 30 ]. Fig. 1 Network of non-coding RNA (ncRNA)-mediated regulation of YAP1 mRNA stability. YAP1 mRNA stability is predominantly controlled through ncRNA-driven competitive endogenous RNA (ceRNA) interactions or direct targeting, coordinated with Hippo pathway signaling to influence cellular phenotypes and tumorigenesis. Among oncogenic ncRNAs, circANKRD42 enhances AJUBA expression by sequestering miR-324-5p, thereby preventing YAP1–LATS interaction, reducing YAP1 phosphorylation, and promoting YAP1 translation; circANKRD42 additionally enhances YAP1 translation through miR-136-5p sequestration. Linc01133 promotes YAP1 nuclear translocation via miR-145-5p sponging. Among tumor-suppressive ncRNAs, MIR22HG stabilizes LATS2 mRNA and protein levels by binding miR-629-5p; LATS2 subsequently phosphorylates YAP1, inducing its degradation and functional inactivation and limiting YAP1–TEAD complex formation. circ-LECRC attenuates miR-135b-5p–mediated repression of the transcription factor KLF4, thereby cooperatively reducing YAP1 transcriptional activity. miR-622 directly targets YAP1 mRNA and decreases YAP1 protein abundance. Created by Figdraw Network of non-coding RNA (ncRNA)-mediated regulation of YAP1 mRNA stability. YAP1 mRNA stability is predominantly controlled through ncRNA-driven competitive endogenous RNA (ceRNA) interactions or direct targeting, coordinated with Hippo pathway signaling to influence cellular phenotypes and tumorigenesis. Among oncogenic ncRNAs, circANKRD42 enhances AJUBA expression by sequestering miR-324-5p, thereby preventing YAP1–LATS interaction, reducing YAP1 phosphorylation, and promoting YAP1 translation; circANKRD42 additionally enhances YAP1 translation through miR-136-5p sequestration. Linc01133 promotes YAP1 nuclear translocation via miR-145-5p sponging. Among tumor-suppressive ncRNAs, MIR22HG stabilizes LATS2 mRNA and protein levels by binding miR-629-5p; LATS2 subsequently phosphorylates YAP1, inducing its degradation and functional inactivation and limiting YAP1–TEAD complex formation. circ-LECRC attenuates miR-135b-5p–mediated repression of the transcription factor KLF4, thereby cooperatively reducing YAP1 transcriptional activity. miR-622 directly targets YAP1 mRNA and decreases YAP1 protein abundance. Created by Figdraw Circular RNAs (circRNAs), owing to their covalently closed structure and enhanced stability, function as central ceRNAs within the Hippo/YAP1 signaling network and are extensively implicated in tumor progression and fibrotic disorders. circRNAs predominantly act by sequestering specific miRNAs, thereby alleviating miRNA-mediated repression of YAP1 mRNA and promoting pro-tumorigenic or pro-fibrotic signaling cascades (Fig.  1 ). In intrahepatic cholangiocarcinoma, circACTN4 sponges miR-424-5p to increase YAP1 expression and recruits YBX1 to activate FZD7 transcription, strengthening YAP1/β-catenin interaction and accelerating tumor progression [ 31 ]. In osteosarcoma, circFAT1 [ 32 ]; in pancreatic ductal adenocarcinoma, hsa_circ_0007367 [ 33 ]; and in endometriosis, circATRNL1 [ 34 ] enhance proliferation, invasion, EMT, or disease advancement through sequestration of miR-375, miR-6820-3p, and miR-141-3p/miR-200a-3p, respectively, thereby relieving repression of YAP1. circANKRD42 exhibits a dual-sponging mechanism: miR-324-5p sequestration upregulates AJUBA, disrupting the interaction between YAP1 and LATS1/2, while miR-136-5p sequestration directly enhances YAP1 protein translation; together, these effects promote lung fibrosis through integration of mechanical stiffness and biochemical signaling [ 35 ]. Certain circRNAs exert inhibitory effects by modulating YAP1-associated regulators. In colorectal cancer, the YAP1-derived circ-LECRC functions as a regulatory brake by sponging miR-135b-5p, thereby relieving suppression of the transcription factor KLF4 and cooperatively restraining YAP1 hyperactivation and downstream oncogene expression [ 36 ]. In small cell lung cancer, extracellular vesicle-derived circSH3PXD2A mitigates chemotherapy resistance through modulation of the miR-375-3p/YAP1 axis [ 37 ]. MicroRNAs (miRNAs) mediate rapid and highly specific post-transcriptional suppression of YAP1 by directly binding its 3' UTR, thereby exerting key regulatory influence in tumorigenesis, therapeutic resistance, and pregnancy-associated disorders. Loss or downregulation of tumor-suppressive miRNAs results in YAP1 derepression, promoting malignant progression and reduced treatment responsiveness (Fig.  1 ). In glioma, miR-622 directly targets the 3' UTR of YAP1 mRNA, markedly reducing YAP1 protein abundance and limiting tumor cell proliferation [ 38 ]. Similarly, miR-590-5p binds the 3' UTR of YAP1 to inhibit translational output. Decreased miR-590-5p expression relieves repression of YAP1, leading to increased levels of YAP1 and downstream target genes, thereby intensifying intestinal inflammatory responses. Through YAP1 inhibition, miR-590-5p induces cell cycle arrest, suppresses proliferation and invasion, and promotes apoptosis in colorectal cancer cells [ 39 ]. In early-onset severe preeclampsia, let-7a cooperatively targets the pro-survival regulators Bcl-xl and YAP1, thereby restraining trophoblast proliferation and cell cycle progression while enhancing apoptotic signaling [ 40 ]. RNA-binding proteins (RBPs) associate with the 3' UTR of YAP1 mRNA and modulate YAP1 abundance by stabilizing the transcript or accelerating its decay (Fig.  2 ). In triple-negative breast cancer, HuR recognizes AREs within the YAP1 transcript and protects it from degradation, promoting YAP1 protein accumulation and subsequent activation of EMT-related pathways that enhance migration and drug resistance [ 41 ]. In contrast, activation of PKC signaling in multiple cancers induces rapid nuclear translocation of hnRNP F, which binds G-tract motifs in the YAP1 3' UTR, shortens mRNA half-life, and reduces YAP1 protein levels, thereby restraining tumor progression [ 42 ]. In breast cancer, decreased circ_0057582 enables direct interaction with hnRNP F, further strengthening hnRNP F binding to the YAP1 3' UTR. This interaction accelerates YAP1 mRNA degradation, downregulates YAP1 and its downstream effector SOX9, suppresses proliferation, migration, and invasion, and enhances apoptotic activity in cancer cells [ 43 ]. During embryonic stem cell differentiation toward the glial lineage, Lin28 directly binds YAP1 mRNA and markedly increases YAP1 protein expression without altering transcriptional output. Subsequent activation of the YAP1/TEAD complex selectively represses glial lineage marker expression [ 44 ]. Fig. 2 Network of coordinated regulation of YAP1 mRNA by RNA-binding proteins (RBPs) and RNA modifications. Stability and translational efficiency of YAP1 mRNA are jointly regulated by RBPs and RNA modifications, contributing to cell proliferation, migration, invasion, and tumor progression. HuR binds YAP1 mRNA and protects it from degradation, whereas Lin28 directly associates with YAP1 mRNA to increase YAP1 protein levels. In contrast, hnRNP F interacts with the 3'UTR of YAP1 mRNA, shortens transcript half-life, and reduces YAP1 protein expression. Regarding RNA modifications, METTL3 catalyzes m6A modification of YAP1 mRNA, enhancing translational efficiency. METTL14 mediates m6A deposition and recruits the reader YTHDF2, promoting YAP1 mRNA degradation. DNMT1 binds the NSUN2 promoter and induces m5C modification within this region, repressing NSUN2 transcription; reduced NSUN2 expression diminishes m5C modification of YAP1 mRNA and impairs YAP1 protein synthesis. Created by Figdraw Network of coordinated regulation of YAP1 mRNA by RNA-binding proteins (RBPs) and RNA modifications. Stability and translational efficiency of YAP1 mRNA are jointly regulated by RBPs and RNA modifications, contributing to cell proliferation, migration, invasion, and tumor progression. HuR binds YAP1 mRNA and protects it from degradation, whereas Lin28 directly associates with YAP1 mRNA to increase YAP1 protein levels. In contrast, hnRNP F interacts with the 3'UTR of YAP1 mRNA, shortens transcript half-life, and reduces YAP1 protein expression. Regarding RNA modifications, METTL3 catalyzes m6A modification of YAP1 mRNA, enhancing translational efficiency. METTL14 mediates m6A deposition and recruits the reader YTHDF2, promoting YAP1 mRNA degradation. DNMT1 binds the NSUN2 promoter and induces m5C modification within this region, repressing NSUN2 transcription; reduced NSUN2 expression diminishes m5C modification of YAP1 mRNA and impairs YAP1 protein synthesis. Created by Figdraw RNA modifications constitute an important epigenetic layer of regulation that shapes gene expression through effects on mRNA stability, translational efficiency, and splicing. Key modification types include m 5 C, m 6 A, m 1 A, m 7 G, and Um (Fig.  2 ). m 6 A refers to methylation at the nitrogen-6 position of adenosine, whereas m 5 C involves methylation at the carbon-5 position of cytosine. In hepatocellular carcinoma, METTL3, a core m 6 A methyltransferase, installs m 6 A marks within the CDS region of YAP1 mRNA, enhancing translational output, activating angiogenesis-associated pathways, and promoting malignant progression [ 45 ]. In triple-negative breast cancer, METTL14 mediates m 6 A deposition within the 3' UTR of YAP1 mRNA, enabling recruitment of the reader protein YTHDF2 and accelerating transcript degradation, thereby limiting cancer stemness [ 46 ]. In osteosarcoma, DNMT1 methylates the NSUN2 promoter and represses its transcription; reduced NSUN2 expression diminishes m 5 C modification of YAP1 mRNA, weakens YAP1 protein synthesis, and increases susceptibility of osteosarcoma cells to chemotherapy-induced apoptosis [ 47 ]. Alternative splicing (AS) processes pre-mRNA through distinct splicing patterns, generating multiple mRNA isoforms that encode functionally diverse proteins. The YAP1 gene undergoes AS to produce eight protein isoforms, with functional heterogeneity primarily determined by variations in the second WW domain (WW2) and the TAD (Table  1 ). The human YAP1 gene comprises nine exons. Exons 2 and 3 jointly encode the first WW domain (WW1) and are separated by the longest intron, whereas exon 4 independently encodes the WW2 domain. Exon 5 contains a short extension designated 5B*, and exon 6 encodes the γ-segment, a 16-amino acid sequence (AMRNINPSTANSPKCQ). Skipping of exon 4 generates the YAP1-1 subgroup, which lacks WW2, whereas exon 4 inclusion yields the YAP1-2 subgroup with intact tandem WW domains. Omission of exon 6 produces the α isoform, preserving a functional leucine zipper motif within the TAD. Inclusion of exon 6 results in the γ isoform, in which insertion of the γ-segment disrupts the leucine zipper motif. Extension of exon 5 introduces four additional amino acids (VRPQ) that similarly disrupt this motif. Concurrent exon 6 skipping with exon 5 extension generates the β isoform, whereas simultaneous inclusion produces the δ isoform [ 48 , 52 ] (Fig.  3 A). These splicing patterns directly determine protein functionality. Isoforms within the YAP1-2 subgroup, containing dual WW domains, interact with PPxY motif-containing components of the Hippo pathway, including LATS1/2 and AMOT [ 53 ], whereas YAP1-1 isoforms with a single WW domain lack the capacity to bind AMOT [ 54 ]. In transcriptional regulation, the γ and δ isoforms display markedly reduced transcriptional activity due to disruption of the leucine zipper motif by the γ-segment or VRPQ insertion, while the α isoform retains transcriptional competence through preservation of an intact leucine zipper structure [ 55 ]. Table 1 Domains, binding partners, functional outputs, disease contexts of YAP1 alternative splicing isoforms Isoform Domain Binding Partner Functional Output Disease Context YAP1-1 Contains WW1 domain; lacks the WW2 domain No specific known binding partners Under basal culture conditions, elevated protein stability and pronounced pro-migratory and pro-invasive activity are observed; binding to AMOT or p73 is absent, stress-induced apoptosis cannot be triggered, and responsiveness to TGF-β, EGF, and bFGF signaling remains limited [ 48 – 50 ] Pancreatic cancer, non-small cell lung cancer, gastric cancer; participates in the EMT process of tumors under normal culture conditions, with higher stability than YAP1-2 [ 49 – 51 ] YAP1-1α Contains WW1 domain; the leucine zipper motif in the TAD is intact No specific known binding partners An intact leucine zipper motif is preserved, maintaining transcriptional competence; SHP2 binding enables suppression of RAS–ERK signaling and downregulation of CCL2 expression [ 16 , 48 ] Multiple types of tumors; involved in tumor signaling pathway regulation and immune microenvironment remodeling [ 16 ] YAP1-1β Contains WW1 domain; the TAD contains a VRPQ insertion No specific known binding partners Insertion of VRPQ disrupts the leucine zipper motif, resulting in diminished transcriptional activity; no definitive isoform-specific function has been established [ 48 ] No specific associated diseases [ 48 ] YAP1-1γ Contains WW1 domain; the TAD contains a γ-segment insertion No specific known binding partners Insertion of the γ-segment disrupts the leucine zipper motif and reduces transcriptional output; a strong pro-EMT phenotype is maintained under standard culture conditions, with limited responsiveness to TGF-β and EGF cues [ 49 , 50 ] Pancreatic cancer, non-small cell lung cancer; mediates the migratory and invasive phenotypes of tumors under normal culture conditions [ 49 , 50 ] YAP1-1δ Contains WW1 domain; the TAD contains VRPQ + γ-segment insertions No specific known binding partners Combined VRPQ and γ-segment insertions completely abolish leucine zipper integrity, leading to marked loss of transcriptional activity [ 48 ] Ovarian diseases; highly expressed in the ovary and placenta, with an unclear function [ 48 ] YAP1-2 Contains dual WW1 + WW2 domains PPxY motif-containing proteins AMOT and p73 binding is retained, enabling induction of stress-associated apoptosis; robust responsiveness to TGF-β, EGF, and bFGF is evident, with EMT and proliferation mediated through AKT-dependent mechanisms [ 48 , 49 , 51 ] Pancreatic cancer, non-small cell lung cancer, gastric cancer; acts as a signal-dependent pro-oncogenic subtype that drives malignant tumor progression [ 49 – 51 ] YAP1-2α Contains WW1 + WW2 domains; the leucine zipper motif in the TAD is intact PPxY motif-containing proteins The leucine zipper motif remains intact, supporting transcriptional activity; SHP2/TAZ binding suppresses RAS–ERK signaling and CCL2 expression, contributing to formation of a “cold” immune microenvironment [ 16 , 51 ] Multiple types of tumors, gastric cancer; promotes tumor growth and enhances bFGF-induced proliferation [ 16 , 51 ] YAP1-2β Contains WW1 + WW2 domains; the TAD contains a VRPQ insertion PPxY motif-containing proteins VRPQ insertion disrupts the leucine zipper motif and impairs transcriptional activity; no clearly defined functional specialization has been identified [ 48 ] No specific associated diseases [ 48 ] YAP1-2γ Contains WW1 + WW2 domains; the TAD contains a γ-segment insertion PPxY motif-containing proteins γ-segment insertion disrupts the leucine zipper motif and attenuates transcriptional activity; SHP2 binding is lost, RAS–ERK signaling and CCL2 expression are enhanced, macrophage recruitment is promoted, and EMT induced by TGF-β and EGF is mediated [ 16 , 49 ] Pancreatic cancer, non-small cell lung cancer; serves as a signal-induced EMT-dominant subtype [ 49 , 50 ] YAP1-2δ Contains WW1 + WW2 domains; the TAD contains VRPQ + γ-segment insertions PPxY motif-containing proteins Dual VRPQ and γ-segment insertions fully disrupt leucine zipper structure, resulting in severe transcriptional impairment [ 48 ] Ovarian and placental diseases; highly expressed in the ovary and placenta, and lowly expressed in leukocytes [ 48 ] Fig. 3 Regulatory network of alternative splicing of YAP1 pre-mRNA and isoform stability. A Alternative splicing of YAP1 pre-mRNA generates eight protein isoforms, with functional heterogeneity primarily determined by structural variation within the WW2 and TAD domains. Exon 4 skipping produces the YAP1-1 subgroup, which lacks the WW2 domain, whereas exon 4 inclusion yields the YAP1-2 subgroup containing tandem WW domains. Differential inclusion or exclusion of exon 6, in combination with exon 5 extension, results in the α, β, γ, and δ isoforms; transcriptional activity of the β/γ/δ variants is attenuated due to insertions that disrupt the leucine zipper motif. At the regulatory level, ( B ) TGF-β treatment reduces ubiquitination of both YAP1-1 and YAP1-2, with a more substantial stabilization observed for YAP1-2, thereby markedly diminishing the stability disparity between the two isoforms. TGF-β further promotes nuclear accumulation of YAP1-2, while only modestly affecting the subcellular distribution of YAP1-1. C Activation of the EGFR–AKT pathway by EGF suppresses ubiquitin-dependent degradation of YAP1-2 and enhances its nuclear enrichment. Created by Figdraw Domains, binding partners, functional outputs, disease contexts of YAP1 alternative splicing isoforms Regulatory network of alternative splicing of YAP1 pre-mRNA and isoform stability. A Alternative splicing of YAP1 pre-mRNA generates eight protein isoforms, with functional heterogeneity primarily determined by structural variation within the WW2 and TAD domains. Exon 4 skipping produces the YAP1-1 subgroup, which lacks the WW2 domain, whereas exon 4 inclusion yields the YAP1-2 subgroup containing tandem WW domains. Differential inclusion or exclusion of exon 6, in combination with exon 5 extension, results in the α, β, γ, and δ isoforms; transcriptional activity of the β/γ/δ variants is attenuated due to insertions that disrupt the leucine zipper motif. At the regulatory level, ( B ) TGF-β treatment reduces ubiquitination of both YAP1-1 and YAP1-2, with a more substantial stabilization observed for YAP1-2, thereby markedly diminishing the stability disparity between the two isoforms. TGF-β further promotes nuclear accumulation of YAP1-2, while only modestly affecting the subcellular distribution of YAP1-1. C Activation of the EGFR–AKT pathway by EGF suppresses ubiquitin-dependent degradation of YAP1-2 and enhances its nuclear enrichment. Created by Figdraw YAP1-1 and YAP1-2 display distinct expression profiles, protein stability, and functional properties, permitting context-dependent regulatory activity within diverse tumor microenvironments. In pancreatic cancer, YAP1-1 demonstrates greater protein stability than YAP1-2 under basal culture conditions, whereas YAP1-2 exhibits substantially higher ubiquitination levels. Exposure to TGF-β markedly reduces ubiquitination of both isoforms, resulting in a more pronounced stabilization of YAP1-2 and a consequent reduction in the stability disparity between the two variants. With respect to subcellular distribution, TGF-β markedly enhances nuclear translocation of YAP1-2 while exerting only limited influence on YAP1-1 localization. Notably, nuclear accumulation of YAP1-2 is substantially greater than its cytoplasmic increase. As a result, YAP1-2 functions as the predominant isoform driving EMT and cellular migration [ 49 ] (Fig.  3 B). In non-small cell lung cancer, EGF activates AKT signaling, thereby suppressing ubiquitination and degradation of YAP1-2. This regulatory mechanism preferentially enhances YAP1-2 protein stability and promotes its nuclear enrichment. Accumulated nuclear YAP1-2 subsequently induces downstream target genes and EMT-associated markers, markedly enhancing migratory and invasive capacities of cancer cells [ 50 ] (Fig.  3 C).

YAP1 regulates glucose, glutamine, and lipid metabolism through interactions with diverse transcription factors, modulation of key metabolic regulators, and signaling pathway crosstalk (Fig.  6 ). Fig. 6 Network of YAP1-mediated reprogramming of glucose, glutamine, and lipid metabolism. YAP1 governs metabolic reprogramming across glucose, glutamine, and lipid pathways through coordinated signaling integration, thereby supporting proliferation, metastasis, and therapeutic resistance and contributing to tumor initiation and progression. In glucose metabolism, hypoxia induces YAP1 dephosphorylation and nuclear translocation, enabling activation of PFKFB3 transcription and enhancement of glycolytic flux. HEXB stabilizes the ITGB1/ILK complex, reducing YAP1 phosphorylation and promoting nuclear accumulation, thereby establishing a positive feedback circuit that induces key glycolytic regulators including GLUT3 and PKM2. Under acute pressure overload, decreased YAP1 phosphorylation promotes formation of a YAP1–TEAD–HIF-1α complex that upregulates GLUT1 expression and further strengthens glycolysis. In glutamine metabolism, oncogenic KRAS mutations suppress SOCS5/6, limiting ubiquitin-dependent degradation of YAP1 and promoting its nuclear localization, which induces transcription of glutamine transporters SLC1A5 and SLC38A2. EphA2 activation of the Rho/ROCK pathway inhibits YAP1 phosphorylation and promotes nuclear translocation, driving expression of SLC1A5 and GLS; SLC1A5 mediates glutamine import, whereas GLS catalyzes conversion of glutamine to glutamate, thereby enhancing uptake and catabolic utilization. In lipid metabolism, palmitic acid increases ZDHHC15 activity, promoting KIBRA palmitoylation and subsequent degradation, which relieves inhibitory phosphorylation of YAP1 and enhances nuclear translocation. The YAP1–TEAD complex induces ZDHHC15 transcription, creating a reinforcing feedback loop that sustains KIBRA degradation, continuously activates YAP1, and upregulates FASN and the fatty acid receptor CD36 to promote metastatic potential. DAGLA catalyzes membrane diacylglycerol hydrolysis to generate 2-AG and free fatty acids; 2-AG inhibits LATS1-mediated phosphorylation of YAP1 while activating PI3K/AKT signaling to promote K63-linked stabilizing polyubiquitination, increasing YAP1 stability and nuclear enrichment. Nuclear YAP1–TEAD subsequently induces PHLDA2 transcription, further elevating FASN and CD36 expression to drive tumor progression. Created by Figdraw Network of YAP1-mediated reprogramming of glucose, glutamine, and lipid metabolism. YAP1 governs metabolic reprogramming across glucose, glutamine, and lipid pathways through coordinated signaling integration, thereby supporting proliferation, metastasis, and therapeutic resistance and contributing to tumor initiation and progression. In glucose metabolism, hypoxia induces YAP1 dephosphorylation and nuclear translocation, enabling activation of PFKFB3 transcription and enhancement of glycolytic flux. HEXB stabilizes the ITGB1/ILK complex, reducing YAP1 phosphorylation and promoting nuclear accumulation, thereby establishing a positive feedback circuit that induces key glycolytic regulators including GLUT3 and PKM2. Under acute pressure overload, decreased YAP1 phosphorylation promotes formation of a YAP1–TEAD–HIF-1α complex that upregulates GLUT1 expression and further strengthens glycolysis. In glutamine metabolism, oncogenic KRAS mutations suppress SOCS5/6, limiting ubiquitin-dependent degradation of YAP1 and promoting its nuclear localization, which induces transcription of glutamine transporters SLC1A5 and SLC38A2. EphA2 activation of the Rho/ROCK pathway inhibits YAP1 phosphorylation and promotes nuclear translocation, driving expression of SLC1A5 and GLS; SLC1A5 mediates glutamine import, whereas GLS catalyzes conversion of glutamine to glutamate, thereby enhancing uptake and catabolic utilization. In lipid metabolism, palmitic acid increases ZDHHC15 activity, promoting KIBRA palmitoylation and subsequent degradation, which relieves inhibitory phosphorylation of YAP1 and enhances nuclear translocation. The YAP1–TEAD complex induces ZDHHC15 transcription, creating a reinforcing feedback loop that sustains KIBRA degradation, continuously activates YAP1, and upregulates FASN and the fatty acid receptor CD36 to promote metastatic potential. DAGLA catalyzes membrane diacylglycerol hydrolysis to generate 2-AG and free fatty acids; 2-AG inhibits LATS1-mediated phosphorylation of YAP1 while activating PI3K/AKT signaling to promote K63-linked stabilizing polyubiquitination, increasing YAP1 stability and nuclear enrichment. Nuclear YAP1–TEAD subsequently induces PHLDA2 transcription, further elevating FASN and CD36 expression to drive tumor progression. Created by Figdraw A principal metabolic role of YAP1 involves promotion of aerobic glycolysis (the Warburg effect) to satisfy cellular energetic and biosynthetic requirements. In acute pressure overload–induced cardiac hypertrophy, a YAP1–TEAD1–HIF-1α complex binds the GLUT1 promoter, inducing GLUT1 expression, increasing glucose uptake, and driving glycolytic accumulation that supports compensatory hypertrophic remodeling [ 83 ]. In diabetic osteoarthritis, TXNIP is negatively regulated by YAP1, reducing GLUT1 internalization, enhancing GLUT1-dependent glycolysis in FLSs (fibroblast-like synoviocytes), and promoting M1 macrophage infiltration [ 84 ]. Regulation of glycolysis by YAP1 also extends to the key enzyme PFKFB3. In ocular neovascular disease, hypoxia triggers YAP1 nuclear translocation and association with TEAD1, activating PFKFB3 transcription and strengthening endothelial glycolytic flux [ 85 ]. In lung cancer, Fascin-mediated activation of YAP1 enables binding to TEAD1/4-responsive elements within the PFKFB3 promoter, increasing PFKFB3 expression, accelerating glycolysis, and supporting tumor growth and metastasis [ 86 ]. YAP1 additionally participates in inhibitory regulatory circuits of glucose metabolism. Wogonin promotes assembly of a KLF11–PPARα–YAP1 complex, thereby suppressing YAP1-driven glycolysis and alleviating atherosclerosis [ 87 ]. In glioblastoma, HEXB stabilizes the ITGB1/ILK complex to activate YAP1, establishing a HEXB–YAP1–HIF1α positive feedback loop that coordinately induces glycolytic genes such as GLUT3 and PKM2 [ 88 ]. During contact inhibition–associated quiescence, YAP1 inactivation reduces expression of glycolytic enzymes including HK2 and PFK1, shifting metabolic reliance from glycolysis toward mitochondrial oxidative pathways [ 89 ]. YAP1 sustains glutamine metabolic homeostasis and supports malignant or pathological states through transcriptional control of glutamine transporters and catabolic enzymes. In liver fibrosis, acting downstream of Hedgehog signaling, YAP1 cooperates with TAZ to bind TEAD response elements within the GLS1 promoter, thereby inducing GLS1 expression and promoting conversion of glutamine to α-ketoglutarate to satisfy the metabolic requirements of myofibroblastic hepatic stellate cells [ 90 ]. In HER2-positive breast cancer, EphA2 activates YAP1 through the Rho/ROCK pathway, after which YAP1 associates with TEAD4 to upregulate the amino acid transporter SLC1A5 and, together with TAZ, regulates GLS, enhancing glutamine uptake and catabolic flux [ 91 ]. In colorectal cancer, oncogenic KRAS mutations reduce YAP1 ubiquitination and increase its stability; YAP1 subsequently partners with TEAD to induce transporters such as SLC1A5 and SLC38A2, enhancing glutamine uptake and activating mTOR signaling [ 92 ]. In pulmonary hypertension, vascular stiffness activates YAP1, enabling TEAD-dependent upregulation of GLS1, promoting glutaminolysis and establishing a vascular stiffness–YAP1–GLS1 positive feedback circuit that accelerates disease progression [ 93 ]. YAP1 also contributes to adaptive responses during glutamine metabolic inhibition. In non-small cell lung cancer, suppression of glutamine utilization decreases cAMP/PKA activity, relieving LATS-mediated restraint of YAP1; subsequent activation induces CTGF expression and enhances ECM (extracellular matrix) deposition [ 94 ]. In breast cancer, YAP1 and TAZ cooperatively induce GOT1 and PSAT1, accelerating glutamine conversion to α-ketoglutarate and supporting tumor growth [ 95 ]. In ischemic stroke, nuclear translocation of astrocytic YAP1 activates β-catenin signaling, upregulating EAAT2 expression to enhance clearance of excess synaptic glutamate and promote glutamine synthetase–mediated conversion. Through these mechanisms, glutamate neurotoxicity is limited, neuronal loss is reduced, and neuroprotection is achieved [ 96 ]. YAP1 links lipid metabolic programs with cellular functional regulation through transcriptional control of enzymes governing lipid synthesis, degradation, and lipid-associated signaling pathways. In hepatocellular carcinoma, the glycolytic enzyme ENO1 promotes nuclear translocation of YAP1. Once nuclear, YAP1 inversely regulates PLCB1 and HPGD, activating arachidonic acid metabolism and driving PGE2 accumulation [ 11 ]. Conversely, 2-AG generated by DAGLA suppresses Hippo signaling and activates PI3K/AKT, promoting YAP1 nuclear localization. Nuclear YAP1 subsequently associates with TEAD2 to induce PHLDA2 expression, thereby accelerating hepatocellular carcinoma progression and conferring resistance to lenvatinib [ 97 ]. In breast and ovarian cancers, palmitic acid activates YAP1, leading to increased expression of the palmitoyltransferase ZDHHC15. ZDHHC15 then mediates palmitoylation of KIBRA, inhibiting Hippo signaling and establishing a ZDHHC15–YAP1 positive feedback circuit that strengthens YAP1-driven lipid metabolic regulation and metastatic potential [ 98 ]. In skeletal muscle, fatty acid oxidation homeostasis is maintained through YAP1-dependent regulation of Idh2, a key TCA cycle enzyme; YAP1 deficiency results in incomplete fatty acid oxidation and subsequent lipotoxic injury [ 99 ]. In NASH, YAP1 forms a transcriptional complex with Foxo1 and NICD, suppressing the cGAS-STING pathway, modulating mitochondrial biogenesis, downregulating genes involved in fatty acid uptake and synthesis, and inducing β-oxidation–related genes, thereby reducing hepatic lipid accumulation [ 100 ].

As a central effector of the Hippo pathway, aberrant YAP1 activation contributes substantially to tumorigenesis, fibrotic disorders, and metabolic disease. Therapeutic approaches directed at this multilayered regulatory network, particularly pharmacologic interventions targeting post-transcriptional and post-translational control, have become a major focus of ongoing investigation (Table  2 ). Table 2 Drugs targeting YAP1 post-transcriptional and post-translational regulatory mechanisms Drug Drug Type Mechanism Disease Mode of Action Evidence Level Specific Target Downstream Effector Targets Impact on Normal Tissue Verteporfin YAP1 inhibitor Directly binds YAP1, blocks YAP1-TEAD interaction Tumors [ 101 – 104 ], cardiovascular diseases [ 105 ], fibrotic diseases [ 106 ] Direct YAP1-TEAD disruptor Preclinical-only YAP1-TEAD transcriptional complex Proliferation targets [ 102 – 105 ]; ERK, SP1 [ 101 ]; AXL, stem cell stemness targets [ 102 ]; apoptosis targets [ 101 , 102 ]; circ_0002722, miR-1305, drug resistance targets [ 103 ]; fibrosis targets, inflammation targets, angiogenesis targetsn [ 106 ] No obvious adverse events [ 102 , 104 – 106 ]; not mentioned [ 101 , 103 ] CA3 YAP1 inhibitor Blocks YAP1-TEAD interaction, inhibits YAP1 nuclear localization colorectal cancer [ 107 ], non-small cell lung cancer [ 108 ], head and neck squamous cell carcinoma [ 109 ], glioma [ 110 ] Direct YAP1-TEAD disruptor Preclinical-only YAP1-TEAD transcriptional complex DUSP1, EGFR/MAPK pathway, autophagy targets [ 108 ]; apoptosis targets [ 108 , 110 ]; EMT targets [ 107 – 110 ]; Nanog [ 107 ]; PPFIBP2 [ 109 ]; invasion/migration targets [ 109 , 110 ]; ferroptosis targets, stem cell stemness targets, PI3K-Akt pathway, Wnt pathway [ 110 ] No obvious adverse events [ 110 ]; not mentioned [ 107 – 109 ] Celastrol YAP1 inhibitor Blocks YAP1-TEAD interaction, inhibits YAP1 nuclear localization Systemic sclerosis [ 111 ], gingival fibrosis [ 112 ] Direct YAP1-TEAD disruptor Preclinical-only YAP1-TEAD transcriptional complex CCN2, COL1A2, TGFβ1, α-SMA, inflammation targets, Wnt pathway [ 111 ]; CCN2, TAZ, pro-fibrotic targets [ 112 ]; extracellular matrix regulatory targets [ 111 , 112 ] Weight loss [ 111 ]; not mentioned [ 112 ] Dihydroartemisinin YAP1 inhibitor Inhibits YAP1 expression and transcriptional activation Hepatocellular carcinoma [ 113 , 114 ] Upstream/parallel modulator Preclinical-only YAP1 Bile Acid—Gut Microbiota—Tumor Immune Regulation Axis [ 113 ]; SLC2A1, glycolysis targets [ 114 ] No obvious adverse events Ivermectin YAP1 inhibitor Inhibits YAP1 mRNA expression and nuclear localization Gastric cancer [ 115 ] Upstream/parallel modulator Preclinical-only YAP1 Proliferation targets No obvious adverse events Ciclesonide YAP1 inhibitor Induces glucocorticoid receptor degradation, reduces YAP1 protein level and nuclear localization Breast cancer [ 116 ] Upstream/parallel modulator Preclinical-only Glucocorticoid receptor YAP1, CSCs targets, stem cell stemness targets No obvious adverse events TED-347 YAP1 inhibitor Covalently binds TEAD4, blocks YAP1-TEAD4 interaction Pancreatic cancer [ 117 ] Direct YAP1-TEAD disruptor Preclinical-only TEAD4 Proliferation/invasion targets Not mentioned Cyclovirobuxine D YAP1 inhibitor Directly binds YAP1, inhibits YAP1 nuclear translocation Breast cancer [ 118 ] Direct YAP1 modulator Preclinical-only YAP1 Mitophagy targets, cell cycle targets, apoptosis targets, EMT targets, autophagy targets No obvious adverse events YAP1 antisense oligonucleotides YAP1 inhibitor Induces YAP1 mRNA degradation Gastric cancer [ 119 ] Upstream/parallel modulator Preclinical-only YAP1 Stem cell stemness targets, proliferation targets No obvious adverse events Celecoxib YAP1 inhibitor Reduces YAP1 protein level, inhibits YAP1 nuclear localization Skin fibrosis [ 120 ] Upstream/parallel modulator Preclinical-only YAP1/TAZ pathway Transdifferentiation targets, ECM targets No obvious adverse events Injinoryeong-san YAP1 inhibitor Inhibits transcriptional activity of YAP1 gene promoter, downregulates YAP1 mRNA and protein expression Steatohepatitis [ 121 ] Upstream/parallel modulator Preclinical-only YAP1/TAZ pathway Lipid metabolism targets, oxidative stress targets, inflammation targets, fibrosis targets, apoptosis targets No obvious adverse events VT103 YAP1 inhibitor Blocks YAP1-TEAD interaction, inhibits YAP1 nuclear localization BRAF V600E mutated lung adenocarcinoma [ 122 ] Direct YAP1-TEAD disruptor Preclinical-only YAP1-TEAD transcriptional complex Apoptosis targets, proliferation targets Not mentioned Hesperidin YAP1 inhibitor Directly binds YAP1, inhibits YAP1 nuclear translocation Vascular neointimal hyperplasia [ 123 ] Direct YAP1 modulator Preclinical-only YAP1 YAP1 O-GlcNAcylation, YAP1-STAT3 complex, VSMCs targets, proliferation targets, migration targets No obvious adverse events Salusin-α YAP1 inhibitor Inhibits YAP1 nuclear translocation Hypertensive nephropathy [ 124 ] Upstream/parallel modulator Preclinical-only Nuclear translocation process of YAP1 ZO-1, inflammation targets No obvious adverse events Kaempferol YAP1 inhibitor Upregulates YAP1 protein level Osteoporosis [ 125 ] Direct YAP1 disruptor Preclinical-only YAP1 Osteogenic targets, osteoclastic targets, NF-κB-p65 pathway, inflammation targets No obvious adverse events bioPROTAC YAP1 inhibitor Directly binds to YAP1, promotes YAP1 ubiquitination and degradation Various tumors [ 126 ] Direct YAP1 degrader Preclinical-only YAP1 Proliferation targets, apoptosis targets, migration/invasion targets, ubiquitination targets No obvious adverse events Schisantherin A YAP1 inhibitor Upregulates YAP1 mRNA and protein expression, enhances YAP1 transcriptional activity Non-small cell lung cancer [ 127 ] Upstream/parallel modulator Preclinical-only YAP1 Ferroptosis targets, cell cycle targets, proliferation targets, apoptosis targets Not mentioned Vitamin D miRNA-targeting Upregulates miR-375, mediates YAP1 suppression Hepatocellular carcinoma [ 128 ] Upstream/parallel modulator Preclinical-only miR-375 YAP1, MTDH, c-MYC, EMT targets Not mentioned Interferon-τ miRNA-targeting Downregulates miR-16a, relieves YAP1 suppression Early pregnancy [ 129 ] Upstream/parallel modulator Preclinical-only miR-16a Proliferation targets, EMT targets, inflammation targets, implantation targets No obvious adverse events Luzindole miRNA-targeting Antagonizes melatonin receptor, elevates miR-143-3p, inhibits YAP1 Myocardial infarction [ 130 ] Upstream/parallel modulator Preclinical-only Melatonin receptor miR-143-3p, YAP1, Ctnnd1, proliferation targets No obvious adverse events Palmitic acid miRNA-targeting F-actin accumulation induces YAP1 dephosphorylation Skeletal myogenesis [ 131 ] Upstream/parallel modulator Preclinical-only miR-429-3p CFL2, YAP1, proliferation targets, myogenic differentiation targets Muscle loss Talazoparib lncRNA-targeting Upregulates lncRNA PLK4, inhibits YAP1 expression and nuclear translocation Hepatocellular carcinoma [ 132 ] Upstream/parallel modulator Preclinical-only PARP1/2, lncRNA PLK4 YAP1, senescence targets, proliferation targets, cell cycle targets No obvious adverse events Simvastatin lncRNA-targeting Downregulates SNHG29, promotes YAP1 degradation Colorectal cancer [ 57 ] Upstream/parallel modulator Clinical-stage evidence HMGCR, lncRNA SNHG29 YAP1, immune checkpoint targets, immune effector molecules No obvious adverse events Curzerene lncRNA-targeting Downregulates lncRNA AFAP1-AS1, inhibits YAP1 mRNA and protein expression Gastric cancer [ 133 ] Upstream/parallel modulator Preclinical-only lncRNA AFAP1-AS1 EMT targets, proliferation targets, migration/invasion targets No obvious adverse events Pantoprazole Ubiquitination-targeting Disrupts OTUB2 binding, promotes YAP1 ubiquitination and degradation Liver fibrosis [ 134 ] Upstream/parallel modulator Preclinical-only OTUB2 YAP1-TEAD2, pro-fibrotic targets, inflammation targets No obvious adverse events Platycodin D Ubiquitination-targeting Promotes YAP1 ubiquitination and degradation Colorectal cancer [ 135 ] Upstream/parallel modulator Preclinical-only LATS2/YAP1 axis Cell cycle targets, proliferation targets, metastasis targets Not mentioned Dapagliflozin Ubiquitination-targeting Inhibits OTUD5-mediated YAP1 degradation Gastric cancer [ 136 ] Upstream/parallel modulator Preclinical-only SGLT2, OTUD5 YAP1, cell cycle targets, EMT targets, proliferation targets, migration targets No obvious adverse events D1 Ubiquitination-targeting Inhibits USP10, promotes YAP1 degradation Hepatocellular carcinoma [ 137 ] Upstream/parallel modulator Preclinical-only USP10 YAP1, cell cycle targets, proliferation targets, apoptosis targets Not mentioned Honokiol Ubiquitination-targeting Binds OTUB2, blocks deubiquitination, promotes YAP1 degradation Ovarian cancer [ 138 ] Upstream/parallel modulator Preclinical-only OTUB2 YAP1, ferroptosis targets, proliferation targets No obvious adverse events Ginkgolic acid Ubiquitination-targeting Inhibits USP10, promotes YAP1 degradation Hepatocellular carcinoma [ 139 ] Upstream/parallel modulator Preclinical-only USP10 YAP1, TEAD4, metabolic targets, proliferation targets, apoptosis targets Not mentioned GSK583 Ubiquitination-targeting Inhibits RIPK2, promotes ITCH-mediated YAP1 degradation Colorectal cancer [ 140 ] Upstream/parallel modulator Preclinical-only RIPK2 YAP1, ITCH, NF-κB pathway, MAPK pathway, metastasis targets No obvious adverse events Moxidectin Ubiquitination-targeting Promotes YAP1 ubiquitination and degradation Glioma [ 141 ] Upstream/parallel modulator Preclinical-only MEK-ERK pathway YAP1, MEK-ERK pathway, proliferation targets, apoptosis targets, stem cell stemness targets, immune targets, immunosuppressive cell targets No obvious adverse events XMU-MP-10 Ubiquitination-targeting Inhibits NEDD4-mediated ubiquitination and degradation of β-TrCP, mediates YAP1 ubiquitination and degradation Breast cancer [ 142 ] Upstream/parallel modulator Preclinical-only NEDD4 β-TrCP, YAP1, ECM targets, immune targets, migration/metastasis targets No obvious adverse events Chidamide Acetylation-targeting Inhibits HDAC10, promotes YAP1 acetylation and nuclear translocation Acute myeloid leukemia [ 143 ] Upstream/parallel modulator Preclinical-only HDAC10 YAP1, DNA damage targets, apoptosis targets Not mentioned Apicidin Acetylation-targeting Inhibits HDAC6, induces YAP1 acetylation, promotes YAP1 intranuclear degradation Myocardial infarction [ 144 ] Upstream/parallel modulator Preclinical-only HDAC6 YAP1, PSME4, differentiation targets No obvious adverse events Nicotinamide Acetylation-targeting Inhibits Sirt2, maintains YAP1 acetylation Hepatocyte regeneration [ 65 ] Upstream/parallel modulator Preclinical-only Sirt2 YAP1, TEAD, cell cycle targets No obvious adverse events Low-dose cisplatin SUMOylation-targeting Downregulates CBX4, inhibits YAP1 SUMOylation, promotes YAP1 phosphorylation and degradation Gastric cancer [ 60 ] Upstream/parallel modulator Preclinical-only CEBPB CBX4, YAP1, senescence targets, proliferation targets No obvious adverse events Drugs targeting YAP1 post-transcriptional and post-translational regulatory mechanisms Small-molecule agents directed against YAP1 exhibit notable activity by disrupting functional domain interactions or altering protein stability. Verteporfin, originally applied in ophthalmic photodynamic therapy, exerts antitumor effects by inhibiting YAP1–TEAD complex assembly, thereby preventing transcriptional activation of downstream oncogenic targets such as CTGF and CYR61 [ 145 ]. Ivermectin reduces YAP1 mRNA translational efficiency, decreases nuclear YAP1 abundance, and suppresses proliferation of gastric cancer cells [ 115 ]. The compound CA3 markedly diminishes YAP1 protein expression in osimertinib-resistant non-small cell lung cancer cells and blocks nuclear translocation. This effect relieves YAP1/YY1-mediated repression of DUSP1, allowing increased DUSP1 protein to bind YAP1 and promote phosphorylation-dependent inactivation. A negative feedback circuit is thereby established, ultimately reversing osimertinib resistance [ 108 ]. The Artemisia annua derivative DHA (dihydroartemisinin) reshapes the immune microenvironment through suppression of YAP1 expression and enhances responsiveness to anti-PD-1 therapy [ 113 ]. miRNAs and lncRNAs dynamically regulate YAP1 mRNA stability and protein activity, thereby expanding opportunities for therapeutic modulation. Vitamin D induces miR-375 expression, suppressing YAP1 and reversing hepatocellular carcinoma resistance to the mTOR inhibitor everolimus while limiting EMT [ 128 ]. IFNτ reduces miR-16a abundance, relieving miR-16a–mediated repression of YAP1 mRNA and increasing YAP1 protein levels, thereby promoting a uterine environment favorable for embryo implantation [ 129 ]. Simvastatin suppresses lncRNA SNHG29, attenuating the YAP1/PD-L1 axis, restricting colorectal cancer cell growth, and improving immune contexture, supporting the potential integration of metabolic and immunotherapeutic strategies [ 57 ]. YAP1 stability and functional activity are governed by coordinated ubiquitination, acetylation, and SUMOylation. Within ubiquitin-dependent regulation, the proton pump inhibitor pantoprazole inhibits the deubiquitinase OTUB2, promoting K48-linked ubiquitination and degradation of YAP1 and alleviating liver fibrosis [ 134 ]. Dapagliflozin reduces OTUD5 expression, enhancing YAP1 ubiquitination and degradation in gastric cancer; combined administration with oxaliplatin improves therapeutic efficacy [ 136 ]. The HDAC6 inhibitor Apicidin induces acetylation of nuclear YAP1, promoting non-ubiquitin-mediated degradation and limiting myocardial fibrosis [ 144 ]. The sirtuin inhibitor NAM selectively blocks Sirt2-mediated deacetylation of YAP1, enhancing K48-linked ubiquitination and degradation in hepatocytes and restraining aberrant liver regeneration [ 65 ]. With respect to SUMOylation, verteporfin not only disrupts YAP–TEAD interactions but also induces SUMOylation of YAP1, altering its nucleocytoplasmic distribution and strengthening antitumor activity in endometrial cancer [ 146 ].

YAP1 (Yes-associated protein 1), a central effector of the Hippo signaling cascade, governs cell proliferation, apoptosis, and organ homeostasis, thereby playing a dual role in tumorigenesis and disease progression [ 1 – 3 ]. Within the canonical Hippo pathway, upstream kinases MST1/2 phosphorylate and activate LATS1/2, which subsequently phosphorylate YAP1 at Ser127. This modification promotes cytoplasmic retention of YAP1 and targets it for proteasomal or lysosomal degradation, thereby restricting nuclear translocation and transcriptional activation. In contrast, inactivation of Hippo signaling leads to YAP1 dephosphorylation and nuclear accumulation, where association with TEAD drives transcription of proliferative genes such as CYR61 and CTGF, contributing to tumorigenesis and tissue hyperplasia [ 4 , 5 ]. Dysregulated YAP1 activation is further refined by multilayered post-transcriptional and post-translational regulatory networks. In addition to canonical phosphorylation, YAP1 expression is modulated at the mRNA level by non-coding RNAs (e.g., miRNA, lncRNA, circRNA), RNA modifications (e.g., m 6 A, m 5 C), and RNA-binding proteins [ 6 – 11 ]. At the protein level, diverse post-translational modifications, including ubiquitination and acetylation, dynamically influence YAP1 stability and functional activity [ 12 , 13 ]. Despite substantial advances in elucidating YAP1 regulation, most prior reviews have concentrated predominantly on canonical Hippo-dependent phosphorylation, with insufficient systematic integration of the coordinated contributions of non-coding RNAs, RNA modifications, and post-translational modifications. The present review provides a comprehensive analysis of RNA-level regulatory synergy, crosstalk among protein modifications, and the barriers to therapeutic development and clinical translation derived from these mechanisms, thereby establishing a conceptual framework for clarifying the molecular basis and targeted intervention strategies of YAP1-driven disorders.