Novel insights into lncRNAs as key regulators of post-translational modifications in cancer: mechanisms and therapeutic potential.

PTMs are covalent and enzymatic alterations that expand the functional diversity of the proteome [ 59 ]. These modifications regulate critical aspects of protein biology, including stability, activity, and interactions, thereby influencing key cellular processes such as signal transduction and gene expression [ 60 – 65 ]. Among the most common PTMs are phosphorylation, ubiquitination, acetylation, and methylation, each mediated by specific enzymes that dynamically alter protein structure and function (Fig.  2 ) [ 64 , 66 – 68 ]. Fig. 2 Proteins undergo a variety of PTMs Proteins undergo a variety of PTMs Aberrant PTMs are closely linked to tumorigenesis. For example, enhancer of zeste homolog 2 (EZH2), a catalytic component of the polycomb repressive complex 2 (PRC2), catalyzes the trimethylation of H3K27, leading to the silencing of tumor suppressor genes and driving cancer progression [ 69 ]. Similarly, CBP/p300 induce H3K27ac at target gene promoters, enhancers, and super-enhancers, thereby activating gene transcription [ 70 ]. While earlier studies suggested that CBP/p300 loss or deletion could promote tumorigenesis. However, more recent evidence indicates that CBP/p300 are overexpressed in various cancers and contribute to oncogene activation [ 71 , 72 ]. Histone deacetylases (HDACs), which remove acetyl groups from histones, are often overexpressed in cancers such as colorectal and breast cancer, repressing tumor suppressor genes and promoting tumorigenesis [ 73 , 74 ]. The disruption of the ubiquitin-proteasome system is another critical factor in cancer development. Another example is that mouse double minute 2 (MDM2) ubiquitinates the tumor suppressor p53, targeting it for degradation. Overexpression of MDM2 reduces p53 levels, thereby impairing apoptosis and enabling cancer cells to evade cell death and proliferate [ 75 ]. Phosphorylation, mediated by kinases, is a fundamental regulatory mechanism for cellular growth and division. Aberrant activation of kinases, such as epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K), is widely recognized as a key driver of cancer initiation and progression. This dysregulation often results from gene amplification, activating point mutations, or sustained phosphorylation of critical tyrosine residues, leading to constitutive activation of downstream signaling cascades, particularly the MAPK and PI3K/AKT pathways, which collectively promote malignant transformation and tumor progression [ 76 , 77 ]. Recently identified PTMs, such as lactylation, are also gaining attention for their roles in cancer biology. Sharing mechanistic similarities with acetylation, lactylation involves enzymes such as p300 and has been shown to modify key proteins like NBS1 and MRE11. This modification enhances DNA repair processes, enabling tumor cells to resist chemotherapy by surviving exposure to DNA-damaging agents [ 78 , 79 ]. Therapeutic strategies targeting PTMs have demonstrated considerable promise in cancer treatment. For example, HDAC inhibitors l such as vorinostat can reactivate silenced tumor suppressor genes, thereby inhibiting tumor growth [ 80 , 81 ]. Similarly, kinase inhibitors, including erlotinib, gefitinib, and imatinib, have been developed to block the aberrant phosphorylation of downstream signaling molecules within the EGFR pathway. These inhibitors have demonstrated efficacy across a range of cancers, including lung cancer, CRC, and chronic myeloid leukemia, by disrupting survival and proliferation pathways [ 82 , 83 ]. Despite these advancements, the clinical application of PTM-targeted therapies remains constrained by several challenges, including acquired drug resistance, limited target specificity, and adverse effects. As such, the development of innovative and more precise therapeutic strategies is urgently required to improve the effectiveness and durability of PTM-based cancer treatments.

The above studies indicate that the PTM networks associated with cancer progression and drug resistance are tightly regulated by lncRNA-mediated PTMs, making lncRNAs potential key therapeutic targets in cancer treatment. In the future, targeting lncRNAs to modulate PTMs or to enhance the efficacy of existing PTM-related drugs could offer promising therapeutic strategies. Multiple strategies targeting lncRNAs are currently under development, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) delivered via liposomes, nanoparticles, or exosomes, and small molecules designed to disrupt lncRNA–protein interactions. In parallel, advances in CRISPR/Cas9 technology offer additional precision tools for editing lncRNA loci or modulating their transcriptional activity, further expanding the therapeutic landscape [ 31 , 191 , 192 ]. These approaches offer promising means to restore PTM homeostasis in cancer. However, clinical translation requires rigorous validation, with careful consideration of delivery efficiency, tissue specificity, and off-target effects. Continued investigation of the lncRNA–PTM axis will be crucial for developing next-generation, precision-targeted cancer therapies. Antisense oligonucleotides (ASOs) are short oligonucleotides, typically 15–22 nucleotides in length, designed to induce gene silencing. ASOs function by binding to complementary RNA sequences via base pairing, thereby modulating the function of target RNAs. They have been widely employed in various mechanisms, including blocking mRNA translation, competitively inhibiting miRNAs, silencing target miRNAs, exon skipping, exon inclusion, and RNase H-mediated target degradation [ 193 , 194 ]. Their ability to specifically bind lncRNA transcripts through complementary base pairing and inhibit gene expression provides a theoretical foundation for the development of lncRNA-targeted therapies [ 195 ]. Specifically, ASOs can knock down tumor-associated lncRNAs in vivo, effectively inhibiting tumor growth. Several studies have demonstrated the therapeutic potential of ASOs in various cancer models. For instance, L. Qu et al. identified lncARSR, a regulator of the AKT signaling pathway, as a therapeutic target for overcoming sunitinib resistance in kidney cancer. LncARSR promotes sunitinib resistance in renal cell carcinoma (RCC), while ASO-mediated knockdown of lncARSR restores tumor sensitivity to sunitinib [ 196 ]. Similarly, J. Liu et al. reported that lncRNA AGPG stabilizes PFKFB3 by inhibiting APC/C-mediated ubiquitination, thereby activating glycolytic flux and promoting cell cycle progression. ASO knockdown of AGPG significantly impaired tumor growth in patient-derived xenograft (PDX) models of esophageal squamous cell carcinoma (ESCC) [ 197 ]. Despite the promising potential of ASO therapies, challenges such as rapid degradation by endonucleases and exonucleases, limited cellular uptake, and cytotoxicity remain significant obstacles. To address these issues, chemical modifications are frequently applied during ASO production to enhance their stability and affinity for target RNA. Although the efficacy of ASO-based therapies has been validated in mouse xenograft models, further improvements are necessary for clinical translation. Encouragingly, numerous ASOs targeting lncRNAs are currently in clinical trials for cancer treatment, demonstrating significant therapeutic promise. lncRNAs possess complex tertiary structures, with conserved regions within their secondary and tertiary domains likely contributing to protein interactions (e.g., stem loops that facilitate protein binding). Despite their significance, research on these structural regions remains limited [ 198 ]. Investigating the structure of cancer-related lncRNAs could aid in identifying small molecules capable of inhibiting their functions. Currently, techniques such as small molecule microarrays and dynamic combinatorial screenings are being employed to identify RNA inhibitors [ 199 ]. Small molecules can disrupt lncRNA-protein interactions, thereby inhibiting their oncogenic activities. For example, the small molecule inhibitor AC1Q3QWB (AQB) disrupts the interaction between lncRNA HOTAIR and EZH2. When combined with tazemetostat, AQB synergistically increases the expression of CDKN1A and SOX17, thereby suppressing endometrial cancer cell proliferation, migration, and invasion [ 200 ]. Targeting the structural domains of lncRNAs with small molecule inhibitors to block their interactions with protein partners represents a promising therapeutic approach. Further exploration of these strategies in clinical trials is warranted to evaluate their potential in cancer treatment. Small interfering RNA (siRNA) represents a novel tool in cancer therapy, capable of targeting specific genes and inducing gene silencing [ 201 ]. However, the clinical application of siRNA is hindered by its susceptibility to degradation and poor cellular uptake, making efficient delivery to tumors a significant challenge. To address these limitations, researchers have developed various nanoparticle (NP)-based delivery systems. Nanotechnology not only protects siRNA during transport but also ensures precise targeting of cancer cells [ 202 ]. Current studies have shown that aptamer-mediated siRNA delivery enables targeted gene silencing and achieves therapeutic effects. These carriers accumulate near tumor cells by recognizing specific tumor surface antigens. Aptamers carrying siRNA or ASOs bind to proteins on the surface of target cells, facilitating endocytosis or membrane fusion, and subsequently releasing siRNA, ASOs, or small molecule drugs into tumor cells [ 203 , 204 ]. Once delivered, siRNAs inhibit the expression of target mRNAs, contributing to tumor suppression [ 205 ]. M. Friedrich et al. utilized siRNA-loaded NPs targeting lncRNA BCMA in a mouse model of TNBC. This approach effectively silenced BCMA expression, leading to a significant reduction in TNBC growth and metastasis [ 206 ]. Similarly, lncRNA DDIT4-AS1, which is highly expressed in TNBC due to H3K27 acetylation at its promoter region, promotes TNBC cell proliferation, migration, and invasion by activating autophagy. Using a siRNA/drug core-shell nanoparticle system, researchers successfully delivered DDIT4-AS1 siRNA to tumor-bearing mice, significantly enhancing TNBC sensitivity to paclitaxel chemotherapy. Notably, the co-delivery of NPs demonstrated stronger antitumor effects in patient-derived breast cancer organoids, underscoring its potential as a targeted therapeutic strategy [ 207 ]. To address the low efficiency of siRNA delivery, Y. Sun et al. developed an innovative in vivo self-assembling siRNA delivery system incorporating H19-specific siRNA sequences, with the mammalian liver serving as the biogenic source. This system effectively inhibited lncRNA H19 expression in CRC, overcoming key barriers to in vivo siRNA delivery [ 201 ]. The approach expanded the range of gene therapy targets and demonstrated superior therapeutic effects across multiple disease models [ 201 , 208 , 209 ]. In the future, targeting lncRNA-mediated PTM networks using these advanced siRNA delivery approaches, combined with conventional anticancer drugs, could offer a promising strategy to enhance cancer treatment outcomes. Restoring or enhancing the tumor-suppressive functions of specific lncRNAs can be achieved by inducing or overexpressing them using plasmid vectors. A novel therapeutic strategy utilizes the BC-819/DTA-H19 plasmid system, which exploits the tumor-specific expression of lncRNA H19. This system incorporates a diphtheria toxin subunit controlled by the H19 promoter. In studies on human bladder cancer, direct injection of the plasmid into tumors resulted in high levels of diphtheria toxin production, effectively reducing tumor size without affecting normal tissues [ 210 ]. Furthermore, BC-819 has demonstrated promising therapeutic outcomes in NSCLC, CRC, pancreatic cancer, and ovarian cancer. These findings suggest that restoring tumor-suppressive lncRNA-mediated PTM networks via plasmid-based approaches holds significant potential as a strategy for cancer therapy. Exosomes are secreted into the extracellular environment through the fusion of intracellular endosomes and the plasma membrane [ 211 ]. Owing to their intrinsic biocompatibility, low immunogenicity, and efficient membrane translocation capacity, exosomes have emerged as superior carriers compared to synthetic nanoparticles such as lipid-based systems, especially in the context of cancer therapy [ 212 , 213 ]. Previous studies have shown that within the TME, both tumor cells and stromal cells can actively secrete exosomes carrying functional lncRNAs, which play critical roles in cancer progression and therapeutic resistance [ 214 – 216 ]. The advent of engineered exosomes capable of encapsulating lncRNA mimics or inhibitors has catalyzed efforts to exploit these vesicles as programmable RNA delivery vehicles. Exosome-mediated lncRNA interference has shown significant potential in halting tumor proliferation and reversing chemoresistance in models of breast, lung, and liver cancers [ 217 , 218 ]. Moreover, cholesterol-enriched exosomes have been shown to deliver siRNAs directly into the cytosol via membrane fusion, thereby bypassing endosomal degradation—a bottleneck for conventional RNA delivery—and providing conceptual insights for future lncRNA-targeting approaches [ 219 ]. Given the complex expression patterns, structural diversity, and subcellular localization of lncRNAs, precise delivery is essential. Advances in RNA nanotechnology have enabled surface engineering of exosomes to enhance cellular uptake and tissue specificity, offering a promising strategy to improve efficacy while reducing off-target effects [ 220 ]. However, clinical translation still faces key challenges, including delivery efficiency, tissue tropism, and RNA loading optimization. Overcoming these barriers will be critical to unlocking the full therapeutic potential of lncRNA-based therapies. Recent advances in CRISPR-based technologies have enabled precise, versatile, and programmable manipulation of lncRNAs, which were once considered elusive due to their non-coding nature, low abundance, and tissue-specific expression. Among them, CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) stand out for their ability to reversibly suppress or activate lncRNA transcription without inducing DNA cleavage [ 50 ]. These systems have been widely used in high-throughput functional screening, with CRISPRa-based SAM systems enabling the identification of immune-regulatory lncRNAs such as IL10RB-DT and LINC01198, which modulate tumor sensitivity to T cell cytotoxicity [ 221 ]. However, Cas9-mediated DNA targeting often introduces off-target effects and may inadvertently perturb neighboring gene expression, thereby limiting its precision and controllability in lncRNA studies. To address these limitations, the CRISPR-Cas13 system has been developed as a transcriptome-targeting platform that enables isoform-specific silencing of lncRNAs at the RNA level without altering genomic architecture. By circumventing the constraints of DNA-level perturbation, Cas13-based approaches have redefined our understanding of lncRNA functionality and established a robust foundation for their therapeutic exploitation [ 222 ]. These technological advances are now fueling translational applications. For instance, in gastric cancer, AAV-mediated CRISPR-Cas9 delivery was used to knock out HCP5-132aa , a micropeptide encoded by a lncRNA, suppressing tumor growth and enhancing ferroptosis sensitivity in patient-derived xenografts [ 223 ]. Integrating CRISPR technologies with organoids, PDX models, and exosome-based delivery systems offers promising avenues for lncRNA-targeted therapies with tissue and context specificity. These advances deepen our understanding of lncRNA biology and pave the way for their translation into precision oncology, with strong potential to reshape future cancer treatment.

The intricate interplay between lncRNAs and PTMs has emerged as a pivotal regulatory axis in cancer biology, orchestrating diverse processes such as proliferation, metastasis, metabolic reprogramming, and therapeutic resistance. Despite significant advances in this field, the functional landscape of lncRNA-mediated PTM interactions remains incompletely understood, largely due to the intrinsic heterogeneity of tumors and the spatiotemporal specificity and functional versatility of lncRNAs across different tissues. A comprehensive and systematic delineation of lncRNA-mediated crosstalk in various tumor types is urgently needed to uncover context-specific regulatory paradigms and therapeutic vulnerabilities. In the future, the construction of high-resolution lncRNA-mediated regulatory atlases and the identification of key effectors and interaction nodes will be essential. With the advent of advanced technologies, such as RNA sequencing, high-resolution mass spectrometry, and CRISPR-based functional screening, there is unprecedented potential to dissect the multilayered mechanisms by which lncRNAs orchestrate diverse PTM events. In particular, understanding how lncRNAs coordinate multiple PTM types may uncover critical hubs governing tumor plasticity. The rapid development of RNA-targeting platforms, including ASOs, siRNAs, engineered exosomes, and CRISPR-Cas systems, has opened new avenues for the precise modulation of lncRNA-mediated networks in vivo, offering promising opportunities for clinical translation and personalized cancer therapy. However, several challenges remain, including low delivery efficiency, off-target effects, poor isoform selectivity, and incomplete functional annotation of lncRNAs. Addressing these technical bottlenecks is crucial for translating lncRNA-mediated research into tangible clinical applications. Ultimately, the integration of RNA biology, proteomics, chemical biology, and nanomedicine will be pivotal in advancing this emerging field. Such multidisciplinary efforts will accelerate the development of next-generation precision therapeutics targeting lncRNA-mediated axes and provide robust theoretical and translational frameworks for combating cancer.

Dysregulated PTMs play a pivotal role in tumorigenesis, as aberrantly modified proteins contribute to various stages of cancer progression, including proliferation, evasion of apoptosis, and metastasis [ 84 , 85 ]. LncRNAs have recently gained attention as key regulators in cancer biology, notably through their ability to modulate diverse types of PTMs [ 54 , 86 , 87 ] (Table 1 ). This interaction constitutes a complex regulatory network that influence cancer cell phenotypes and potentially affect therapeutic outcomes. Rather than serving as passive transcriptional byproducts, lncRNAs actively fine-tune protein function to promote tumor growth, sustain survival, facilitate metastasis, and reprogram cellular metabolism [ 12 , 88 ]. Table 1 lncRNA-mediated PTMs in cancers lncRNA Expression (Up/Down) Targeted Protein/Pathway Cancers Regulatory effect Ref lncRNA-mediated ubiquitination modification in cancers LINC01016 Up DHX9 BRCA Promoting BC proliferation and invasion through stabilized DHX9 via blocking its interaction with RFFL [ 89 ] RIME Up MLL1 OS Facilitating immune evasion and tumor development [ 90 ] LINC01537 Up RIPK4 GC Promoting GC metastasis and tumorigenesis through blocking the interaction of RIPK4 and TRIM25 thus reducing its ubiquitination degradation [ 91 ] TINCR Up PD-L1 BRCA Promoting PD-L1 expression through miR-199a-5p/ USP20 axis [ 92 ] CERS6-AS1 Up P53 HCC Inhibiting the expression of p53 throughmiR-30b-3p/MDM2 axis [ 93 ] LINC00955 Down Sp1/CDK2 CRC Promoting the binding of TRIM25 to Sp1, thereby further increasing the ubiquitination of CDK2 [ 94 ] DLGAP1-AS2 Up ELOA CRC Promoting CRC tumorigenesis and metastasis through interacting with ELOA and increasing its ubiquitination degradation mediated by Trim21 [ 95 ] NRON Up P53/RB1/NFAT1 BRCA Inducing MDM2 and MDMX heterogenous dimerization, thereby enhancing the E3 ligase activity [ 96 ] TYMSOS Up ULBP3 BRCA Promoting tumor growth and repressing NK cell cytotoxicity [ 97 ] lncRNA-mediated SUMOylation modification in cancers ELNAT1 Up hnRNPA1 BLCA Promoting lymphangiogenesis and lymph node metastasis through UBC9/SOX18 regulatory axis [ 102 ] FRMD6-AS1 Up HIF-1α HCC Suppressed HIF-1α SUMOylation to accelerate HCC cell migration and stemness [ 103 ] PSTAR Down P53 HCC Binding to hnRNP K and enhancing its SUMOylation, ultimately leads to the accumulation and transactivation of p53 [ 104 ] MILIP Up P53 PANCAN Restraining p53 SUMOylation through TRIML2 and facilitating p53 polyubiquitination degradation [ 94 ] SDCBP2-AS1 Down hnRNP K/β-catenin GC Increasing ubiquitination of hnRNP K and β-catenin, thus suppressing tumorigenesis and metastasis [ 101 ] lncRNA-mediated phosphorylation modification in cancers CSNK1G2-AS1 Up AKT TGCT Promoting development and metastasis [ 108 ] LINC01060 Up AKT OS Increasing Akt phosphorylation [ 109 ] GAL1 Down AKT OS Inhibiting Akt phosphorylation [ 110 ] DUXAP10 Up GPR39 HCC Sponging miR-1914 to inhibit HCC progression through targeting GPR39-mediated PI3K/AKT/mTOR pathway [ 111 ] DICER1-AS1 Up ERK1/2 CRC Promoting ERK1/2 phosphorylation, and sequentially activates the MAPK/ERK signaling pathway [ 112 ] ZFAS1 Up ZEB1 PC Promoting EMT and metastasis under metabolic stress conditions [ 113 ] LINC00880 Up AKT LUAD Increasing CDK1 kinase activity and the interaction of CDK1 and PRDX1, ultimately increasing AKT phosphorylation [ 114 ] PVT1 Up TAZ RCSC Promoting RCSC stemness [ 115 ] RP11-296E3.2 Up STAT3 CRC Promoting the CRC cell proliferation and migration [ 117 ] PVT1 Up STAT5B BLCA Promoting the nucleus translocation of STAT5B further trigger bladder cancer progression [ 116 ] GMDS-AS1 Up STAT3 CRC Stabilizing STAT3 mRNA and upregulating phosphorylated STAT3 [ 118 ] lncRNA-mediated acetylation modification in cancers HOXC-AS3 Up ACSL4 NSCLC Increasing EP300's stability and mRNA level, enhancing ferroptosis in NSCLC cells [ 123 ] DLX6-AS1 Up DLX6 UCEC Upregulating DLX6 expression and promoting the progression of endometrial cancer [ 125 ] SAMMSON Up Sp1 PTC Increasing the transcriptional activation of Sp1, thereby facilitating PTC progression [ 126 ] LINC00472 Down ITGB8 RCC Inhibited cell proliferation and enhancing intercellular adhesion [ 224 ] LINC00857 Up ANXA11 CRC Promoting SLC1A5-mediated glutamine transport [ 225 ] RP11.367G18.1 Up RP11-367G18.1 variant 2 RCC Inducing EMT and enhancing cell migration and invasion [ 129 ] SNHG29 Down AML-associated genes AML Inhibiting AML cell proliferation and decreasing sensitivity to cytarabine [ 122 ] PACERR Up PACERR PDAC Activating the KLF12/p-AKT/c-myc pathway, thus increasing M2 polarization [ 124 ] PACERR Up PACERR/PTGS2 PDAC Promoting the M2 polarization [ 130 ] lncRNA-mediated histone methylation modification in cancers ANRIL Up p21/CDKN1A ATL Inhibiting p21/CDKN1A transcription and supporting HTLV-1 infected cell proliferation [ 132 ] FEZF1-AS1 Up P21 GC Inhibiting the P21 promoter H3K4me2 demethylation mediated by LSD1, further promoting GC cells proliferation [ 133 ] ARHGAP27P1 Down p15/p16/ p57 GC Promoting the progression of GC [ 135 ] LINC00478 Up MMP9 BLCA Inhibiting tumor growth and metastasis [ 136 ] TP73- AS1 Up TP73 CRC Influencing TP73 transcription and CRC malignancy [ 137 ] NEAT1 Up Cul4A CRC Inhibiting the expression of KDM5A and Cul4A thereby in turn activating the Wnt pathway [ 134 ] lncRNA-mediated DNA methylation modification in cancers ZNF667-AS1 Up ZNF667/E-cadherin ESCC Recruiting TET1 to inhibit 5-mC DNA methylation and cooperating with UTX to remove H3K27me3 histone marks [ 139 ] TINCR Up miR-503-5p BRCA Recruiting DNMT1 to methylate the miR-503-5p promoter; Sponging miR-503-5p to upregulate EGFR [ 140 ] HOTAIR Up PTEN CML Promoting DNMT1-mediated PTEN methylation, repressing PTEN expression and driving CML progression. [ 141 ] LINC00662 Up MAT1A/AHCY HCC Reprogramming SAM/SAH metabolism, thereby reshaping promoter methylation and activating HCC oncogenes. [ 142 ] lncRNA-mediated other types of modification in cancers LINC01296 Up GALNT3 CRC Sponge miR-26a to elevating MUC1 expression, thereby activating PI3K/AKT pathway activity. [ 146 ] LINC01127 Up MAP4K4 GSC Recruiting POLR2A to cis-activate MAP4K4, thereby promoting GBM cell self-renewal via the JNK/NF-κB axis [ 147 ] LINC00152 Up / CRC Promoting the migration and invasion of CRC [ 163 ] DUXAP8 Up SLC7A11 HCC promoting the palmitoylation of SLC7A11 and prevening its lysosomal degradation [ 143 ] PVT1 Up YKT6 Pan-Cancer Promoting exosome secretion and supporting tumor progression [ 171 ] GLTC Up LDHA PTC Enhancing LDHA enzymatic activity, thereby contributing to PTC progression [ 145 ] LINC00922 Up SIRT3 CRC Upregulating H3K27 crotonylation at the ETS1 promoter, facilitating CRC metastasis [ 144 ] lncRNA-mediated PTMs in cancers Given the pivotal role of PTMs in cancer, lncRNAs have been proposed as potential therapeutic targets. Intervening in lncRNA-mediated PTM pathways could present novel opportunities to disrupt oncogenic signaling and restore tumor suppressor activity. However, despite growing evidence, the precise molecular mechanisms by which lncRNAs regulate PTMs remain incompletely understood and require more comprehensive mechanistic investigations. lncRNAs play a significant role in modulating protein ubiquitination in cancer via multiple molecular mechanisms (Fig.  3 ). One prominent mechanism involves ubiquitination is by interacting with E3 ubiquitin ligases, thereby stabilizing their ubiquitinated targets. For example, Y. Sun et al. demonstrated that the LINC01016/DHX9/PI3K/AKT axis plays a critical role in breast cancer (BRCA) with lymph node metastasis. Mechanistically, LINC01016 binds to the E3 ubiquitin ligase RFFL, preventing RFFL from binding to DHX9 and inhibiting its degradation [ 89 ]. Similarly, research has shown that exosome transmission and TNF-α stimulation upregulate the lncRNA RIME in tumor cells. RIME binds to ASB2, blocking the ubiquitin-mediated degradation of MLL1. This stabilization resulting in elevated expression of immune checkpoint markers PD-L1 and IDO-1, facilitating immune evasion and tumor progression [ 90 ]. Furthermore, G.Y. Zhong et al. revealed that LINC01537 stabilizes RIPK4 by preventing its interaction with TRIM25, thereby reducing its ubiquitination and degradation. This stabilization enhances NF-κB pathway activity, promoting GC metastasis and tumorigenesis [ 91 ]. Collectively, these findings indicate that lncRNAs enhance protein stability by blocking the interactions between E3 ligases and their ubiquitinated substrates. In addition to directly interacting with E3 ligases, lncRNAs can also indirectly regulate ubiquitination by acting as competing endogenous RNAs (ceRNAs). For instance, lncRNA TINCR acts as a sponge for miR-199a-5p, modulating the ubiquitination of PD-L1 and influencing immune evasion in breast cancer [ 92 ]. Similarly, B. Xu et al. identified CERS6-AS1, which sponges miR-30b-3p to elevate MDM2 levels. This elevation promotes MDM2-mediated ubiquitin-dependent degradation of p53, driving HCC progression [ 93 ]. These studies underscore the multifaceted roles of lncRNAs in orchestrating ubiquitination networks in cancer. Fig. 3 lncRNA-mediated ubiquitination modification influences cancer progression lncRNA-mediated ubiquitination modification influences cancer progression lncRNAs can also function as molecular scaffolds, facilitating the physical interaction between E3 ubiquitin ligases and their substrates, thereby influencing protein stability and turnover. For example, G. Ren et al. demonstrated that LINC00955 acts as a scaffold promoting the interaction between TRIM25 and Sp1, which enhances Sp1 ubiquitination and subsequent degradation. This leads to reduced CDK2 expression, induces G0/G1 phase cell cycle arrest, and inhibits CRC cell proliferation both in vitro and in vivo [ 94 ]. Similarly, X. Wang et al. reported that DLGAP1-AS2 facilitates TRIM21-mediated ubiquitination and degradation of Elongin A (ELOA), contributing to CRC tumorigenesis and metastasis [ 95 ]. In another study, the lncRNA NRON was found to interact with both MDM2 and MDMX (also known as MDM4) through distinct stem-loop structures, promoting their heterodimerization. This heterodimer enhances the E3 ligase activity of MDM2, resulting in the degradation of tumor suppressors such as p53, RB1, and NFAT1, ultimately facilitating tumor progression [ 96 ]. Additionally, Zhang et al. revealed that lncRNA TYMSOS enhances SYVN1-mediated proteasomal degradation of ULBP3, an immune-activating ligand. This degradation impairs NK cell cytotoxicity and promotes tumor immune evasion, underscoring the immunomodulatory functions of lncRNAs in cancer [ 97 ]. In summary, aberrant regulation of the ubiquitination system represents a critical mechanism in tumorigenesis, with lncRNAs exerting multifaceted control over protein degradation pathways. While targeting lncRNA-mediated ubiquitination has emerged as a potentially valuable therapeutic strategy, most current findings remain preclinical. Further studies are required to elucidate the specificity, safety, and translational potential of these lncRNA-mediated mechanisms in human cancers. SUMOylation, a small ubiquitin-like PTM, has emerged as a distinct and important PTM regulatory mechanism. SUMO (Small Ubiquitin-like Modifier) proteins are covalently attached to lysine residues of target proteins, leading to alterations in their conformation, stability, activity, or subcellular localization. Although SUMOylation shares enzymatic similarities with ubiquitination, their functional consequences often differ: while ubiquitination typically marks proteins for proteasomal degradation, SUMOylation tends to stabilize proteins or modulate their regulatory functions [ 98 , 99 ]. Dysregulation of SUMOylation has been implicated in tumor development and progression by influencing various oncogenic signaling pathways [ 100 ]. Emerging studies suggest that lncRNAs can modulate protein SUMOylation via multiple mechanisms, including the regulation of SUMO pathway enzymes (e.g., SUMO E3 ligases and deSUMOylases), acting as molecular scaffolds, or competitively binding to SUMOylation sites on target proteins [ 101 , 102 ]. Through these mechanisms, lncRNAs may exert either oncogenic or tumor-suppressive functions, adding another layer of complexity to PTM regulation in cancer. Therefore, the following section focuses specifically on the recent advances in lncRNA-mediated SUMOylation in cancer (Fig.  4 ). Fig. 4 lncRNA-mediated SUMOylation modification influences cancer progression lncRNA-mediated SUMOylation modification influences cancer progression In one study, C. Chen et al. reported that ELNAT1 upregulates UBC9 expression, which catalyzes the SUMOylation of hnRNPA1 at lysine 113. This modification facilitates ESCRT complex recognition, promoting hnRNPA1 packaging into extracellular vesicles (EVs). These EVs, enriched with ELNAT1, are taken up by human lymphatic endothelial cells (HLECs), where they activate SOX18 transcription and promote lymphangiogenesis [ 102 ]. Similarly, W. Sun et al. found that lncRNA FRMD6-AS1 enhances the activity of the SENP1, thereby reducing the SUMOylation of HIF-1α, which accelerates HCC cell migration and stemness [ 103 ]. G. Qin et al. discovered that a novel lncRNA, PSTAR, promotes p53 accumulation and activity by enhancing the SUMOylation of hnRNP K. PSTAR disrupts the interaction between hnRNP K and SENP2, thereby stabilizing its interaction with p53 and inducing cell cycle arrest [ 104 ]. Conversely, Feng et al. demonstrated that c-Myc represses p53 SUMOylation through the lncRNA MILIP, which binds TRIML2 (a SUMO E3 ligase) and inhibits its function. This leads to enhanced p53 polyubiquitination and proteasomal degradation [ 99 ]. In another example, J. Han et al. showed that lncRNA SDCBP2-AS1 suppresses SUMOylation by blocking the primary SUMOylation site on hnRNP K. This results in increased ubiquitination of both hnRNP K and β-catenin, ultimately suppressing GC progression and metastasis [ 101 ]. In conclusion, lncRNAs play crucial and diverse roles in the regulation of protein SUMOylation. Their dysregulation can significantly impact the functional integrity of tumor suppressor pathways and oncogenic networks. While targeting lncRNA-mediated SUMOylation offers an intriguing therapeutic avenue, further in-depth mechanistic and translational studies are necessary to validate its clinical potential. Phosphorylation is a key PTM involved in regulating diverse cellular processes such as cell survival, proliferation, cell cycle progression, and energy metabolism, all of which are critical in cancer development and progression [ 1 , 105 ]. This modification most commonly occurs on serine residues, followed by threonine and tyrosine [ 106 , 107 ]. Recent studies have demonstrated that lncRNAs play significant roles in regulating protein phosphorylation and thereby influencing oncogenic signaling cascades ( Fig.  5 ) . For instance, overexpression of lncRNA CSNK1G2-AS1 significantly upregulates AKT expression and phosphorylation, promoting testicular germ cell tumor (TGCT) development and metastasis [ 108 ]. Similarly, LINC01060 enhances osteosarcoma growth by promoting PI3K and AKT phosphorylation, while lncRNA GAL1 acts as a suppressor of the PI3K/AKT pathway in the same cancer context [ 109 , 110 ]. These findings suggest that lncRNA-mediated regulation of phosphorylation is central to modulating oncogenic pathways, particularly the PI3K/AKT/mTOR and MAPK pathways. Fig. 5 lncRNA-mediated phosphorylation modification influences cancer progression lncRNA-mediated phosphorylation modification influences cancer progression lncRNAs can also modulate phosphorylation indirectly by functioning as ceRNAs. For example, lncRNA DUXAP10 sponges miR-1914, thereby suppressing phosphorylation within the PI3K/AKT/mTOR pathway in [ 111 ]. In CRC, lncRNA DICER1-AS1 sponges miR-650, leading to enhanced MAPK1 phosphorylation and activation of the MAPK/ERK pathway, thereby supporting tumor progression [ 112 ]. In addition to acting as ceRNAs, lncRNAs can serve as molecular scaffolds to facilitate interactions between kinases and their substrates. lncRNA ZFAS1 enhances the interaction between AMPK and ZEB1, promoting ZEB1 phosphorylation and stabilization under metabolic stress, which contributes to EMT and metastasis in pancreatic cancer [ 113 ]. Likewise, LINC00880 binds to CDK1, enhancing its kinase activity and its interaction with PRDX1, ultimately promoting AKT phosphorylation and driving lung adenocarcinoma (LUAD) progression [ 114 ]. Direct physical interactions between lncRNAs and proteins also influence phosphorylation events. For instance, PVT1 has been shown to enhance phosphorylation of signaling molecules, thereby promoting the stemness and therapy resistance of renal cancer stem cells (RCSCs) [ 115 ]. Additionally, PVT1 facilitates STAT5B phosphorylation and nuclear translocation by inhibiting its ubiquitination, promoting bladder cancer progression [ 116 ]. lncRNA RP11-296E3.2 interacts with YBX1, facilitating STAT3 phosphorylation and promoting CRC cell proliferation and migration [ 117 ]. Furthermore, Moreover, lncRNAs can modulate phosphorylation levels by stabilizing mRNAs that encode phosphorylated proteins. For instance, lncRNA GMDS-AS1 binds to the RNA-binding protein HuR to stabilize STAT3 mRNA, leading to increased total and phosphorylated STAT3 levels and sustained activation of the STAT3 pathway in CRC [ 118 ]. Overall, aberrant phosphorylation-driven signaling is a hallmark of cancer, and its dysregulation contributes substantially to tumorigenesis. lncRNAs have emerged as critical regulators of these processes through both direct and indirect mechanisms. While targeting lncRNA-mediated phosphorylation appears to be a promising strategy for precision oncology, the specificity, context-dependence, and translational potential of these pathways remain to be fully elucidated. Acetylation is a crucial PTM that regulates protein function, chromatin architecture, and gene expression. Specifically, histone acetylation facilitates the relaxation of chromatin structure by promoting the dissociation of DNA from histone octamers. This process enhances accessibility for transcription factors and co-regulators to bind to specific genomic loci, thereby initiating gene transcription [ 119 , 120 ]. The dynamic balance of histone acetylation is primarily governed by histone acetyltransferases (HATs), such as p300/CBP, and histone deacetylases (HDACs) [ 121 ]. Increasing evidence indicates that lncRNAs are involved in the regulation of histone acetylation by interacting with key epigenetic enzymes, particularly p300 ( Fig.  6 ) [ 122 – 126 ]. For example, Z. Shi et al. reported that lncRNA HOXC-AS3 binds to EP300, stabilizes its protein levels, and upregulates its mRNA expression, thereby inhibiting ferroptosis in non-small cell lung cancer (NSCLC) [ 123 ]. In another example, lncRNA DLX6-AS1 was shown to recruit p300 to the promoter of DLX6, promoting endometrial cancer progression through transcriptional activation [ 125 ]. Likewise, SAMMSON, a lncRNA transcriptionally induced by oncogenic Sp1, functions as a scaffold to recruit p300, resulting in increased H3K9ac and H3K27ac levels at the Sp1 promoter. This enhances Sp1 transcription and contributes to the progression of PTC [ 126 ]. Other lncRNAs, including LINC00472, RP11-367G18.1, LINC00857, and SNHG29, have also been implicated in p300-mediated histone acetylation in various cancer types [ 122 , 127 – 129 ]. Emerging evidence suggests that lncRNAs also influence immune cell polarization through epigenetic mechanisms. For example, lncRNA PACERR interacts with KLF12 to recruit EP300 into the nucleus, enhancing histone acetylation and activating the KLF12/p-AKT/c-MYC pathway, which contributes to M2 macrophage polarization [ 124 ]. Furthermore, PACERR binds to CTCF and recruits p300 to the promoter regions of PACERR and PTGS2, thereby promoting M2 polarization of tumor-associated macrophages (TAMs) in pancreatic ductal adenocarcinoma (PDAC) [ 130 ]. Fig. 6 lncRNA-mediated acetylation modification influences cancer progression lncRNA-mediated acetylation modification influences cancer progression These findings highlight the critical role of lncRNAs in regulating gene expression via epigenetic modulation of histone acetylation. Notably, recent studies have revealed that acetylation-related enzymes such as p300 and SIRT1 also mediate a novel histone mark–lactylation, which links metabolism to gene regulation. However, whether lncRNAs can function as upstream regulators of lactylation remains largely unexplored. Methylation is a vital epigenetic modification that regulates gene transcription by altering chromatin structure and influencing the recruitment of transcription factors and co-regulators. This process is primarily governed by histone methyltransferases (HMTs), which catalyze the addition of methyl groups, and histone demethylases (HDMs), which remove them [ 121 , 131 ]. Recent studies have highlighted the role of lncRNAs as crucial regulators of histone and DNA methylation, affecting various aspects of tumor biology (Fig.  7 ). Fig. 7 lncRNA-mediated methylation modification influence cancer progression lncRNA-mediated methylation modification influence cancer progression In adult T-cell leukemia (ATL), lncRNA ANRIL was shown to interact with EZH2, forming a functional complex that enhances the DNA-binding activity of p65, thereby activating NF-κB signaling. Concurrently, ANRIL promotes H3K27 trimethylation at the p21/CDKN1A promoter, leading to transcriptional repression of p21 and proliferation of HTLV-1-infected cells [ 132 ]. Similarly, lncRNA FEZF1-AS1 is overexpressed in GC and correlates with poor prognosis. FEZF1-AS1 inhibits lysine-specific demethylase 1 (LSD1), thereby preventing H3K4me2 demethylation at the p21 promoter and enhancing GC cell proliferation [ 133 ]. In CRC, NEAT1 inhibits lysine demethylase 5 A (KDM5A), promoting Wnt pathway activation by reducing Cul4A expression through H3K4me3 demethylation [ 134 ]. Additionally, lncRNAs can recruit demethylases directly to gene promoters to regulate transcription. For example, ARHGAP27P1 recruits jumonji domain-containing protein 3 (JMJD3) in GC cells, promoting H3K27me3 demethylation and upregulating cell cycle inhibitors such as p15, p16, and p57 [ 135 ]. Similarly, LINC00478 promotes bladder cancer progression by recruiting KDM1A to the MMP9 promoter, reducing H3K4me1 levels and modulating genes involved in tumor growth and metastasis [ 136 ]. In CRC, TP73-AS1 recruits KDM5A to activate TP73 expression, contributing to tumor progression [ 137 ]. Beyond histone modifications, lncRNAs also regulate DNA methylation by interacting with DNA methyltransferases (DNMTs) and TET family dioxygenases. These interactions guide the deposition or removal of 5-methylcytosine (5-mC) at promoter regions and shape the epigenetic landscape of gene expression [ 138 ]. For instance, ZNF667-AS1 interacts with UTX, reducing H3K27me3 levels at the promoters of ZNF667 and E-cadherin. It further binds directly to these loci and recruits TET1 to remove 5-mC marks, synergistically activating their transcription [ 139 ]. In BRCA, TINCR recruits DNMT1 to the miR-503-5p promoter, promoting 5-mC deposition and silencing of miR-503-5p, which in turn activates the EGFR/JAK2/STAT3 signaling cascade and drives tumor progression [ 140 ]. Similarly, in chronic myeloid leukemia, HOTAIR interacts with DNMT1 to enhance methylation of the PTEN promoter, repressing its expression and promoting leukemogenesis, while silencing HOTAIR reverses this effect [ 141 ]. Additionally, lncRNAs can modulate global DNA methylation by regulating the metabolic balance of the methyl donor S-adenosylmethionine (SAM) and its by-product S-adenosylhomocysteine (SAH). LINC00662, for example, affects the expression of MAT1A and AHCY, altering the SAM/SAH ratio, inducing global hypomethylation, and activating oncogenic pathways [ 142 ]. In summary, lncRNAs have emerged as central epigenetic regulators of both histone and DNA methylation. By recruiting or modulating the activity of chromatin-modifying enzymes and influencing methylation-related metabolites, lncRNAs orchestrate fine-tuned control over gene expression. Their dual roles in shaping the epigenetic landscape underscore their growing potential as therapeutic targets in cancer. Nevertheless, further studies are required to determine the function of lncRNA-mediated methylation in different cancer types. PTMs such as glycosylation, lactylation, and palmitoylation are closely tied to metabolic substrate availability, highlighting the critical crosstalk between metabolic reprogramming and cancer progression. Mounting evidence suggests that lncRNAs play pivotal roles in mediating this interplay. Metabolic shifts can modulate PTMs through lncRNA-dependent mechanisms, forming a feedback loop between metabolism and epigenetic regulation. Beyond well-characterized PTMs, lncRNAs have also been implicated in the regulation of emerging modifications, including glycosylation, lactylation, palmitoylation, succinylation, and crotonylation [ 143 – 147 ] (Fig.  8 ). Understanding the intricate regulatory networks connecting lncRNAs and these PTMs not only deepens our insights into cancer metabolism and epigenetics but also opens promising avenues for the development of novel therapeutic strategies. Fig. 8 Other types of lncRNA-mediated PTMs influence cancer progression Other types of lncRNA-mediated PTMs influence cancer progression Glycosylation is one of the most prevalent PTMs, primarily occurring in the endoplasmic reticulum and Golgi apparatus [ 148 ]. It is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which respectively add and remove O-GlcNAc from serine/threonine residues using UDP-GlcNAc as the donor molecule [ 149 , 150 ]. Glycosylation extensively affects a variety of proteins and associated cellular processes, playing a vital role in the regulation of cellular functions [ 151 ]. Aberrant O-GlcNAcylation is frequently observed in various tumors and contributes to oncogenesis, proliferation, and metastasis [ 152 , 153 ]. lncRNAs have emerged as crucial regulators of glycosylation, influencing cancer progression through glycosylation-related pathways. For instance, the linc01296/miR-26a/O-glycosylated MUC1 regulatory network modulates CRC progression via the PI3K/AKT signaling pathway [ 146 ]. Beyond their regulatory roles, glycosylation-associated lncRNAs have been identified as independent prognostic markers in tumors. Several tumor risk models based on glycosylation-related lncRNAs have demonstrated potential as novel biomarkers and therapeutic targets [ 154 , 155 ]. Although research on O-GlcNAcylation remains in its early stages, growing evidence highlights the potential of lncRNAs as regulators of glycosylation. Targeting glycosylation-related lncRNAs could offer promising avenues for novel cancer therapies and prognostic tools. The Warburg effect, a hallmark of cancer, describes the preference of tumor cells for glycolysis over oxidative phosphorylation, even in the presence of sufficient oxygen. This metabolic reprogramming leads to the accumulation of lactate, a key glycolytic metabolite that is frequently upregulated in tumors [ 156 , 157 ]. Despite its established role in cancer metabolism, the precise contribution of lactate to tumor progression remains unclear. In a landmark 2019 study, Zhao et al. identified lactylation, a PTM of lysine residues, as a novel mechanism by which lactate influences gene expression, particularly under hypoxic conditions characterized by lactate accumulation [ 158 ]. This discovery positions lactylation as a critical link between metabolic reprogramming and epigenetic regulation in cancer [ 159 ]. The identification of lactylation has expanded the scope of epigenetic regulation. Key enzymes such as P300/CBP and Sirt1, known for their roles in acetylation, have also been implicated in mediating lactylation under specific conditions [ 160 – 162 ]. Of particular interest is the potential involvement of lncRNAs in recruiting these lactylation enzymes to specific genomic loci. Acting as molecular scaffolds, lncRNAs may direct lactylation machinery to precise locations, suggesting regulatory crosstalk between lncRNAs and acetyltransferases that warrants further investigation. Emerging evidence highlights the intricate interplay between lncRNAs and lactylation in tumor progression. For instance, L. Li et al. demonstrated that activation of the NF-κB pathway in glioblastoma (GBM) cells enhances the Warburg effect, leading to histone H3 lactylation at the LINC01127 promoter. This modification promotes LINC01127 transcription, forming a positive feedback loop that sustains the Warburg effect and enhances glioblastoma stem cell (GSC) stemness [ 147 ]. Similarly, lipopolysaccharide (LPS) induces histone lactylation at the LINC00152 promoter, reducing the binding affinity of the repressor YY1, thereby upregulating LINC00152 expression and driving tumor growth [ 163 ]. Unlike other PTMs, lactylation is unique in that its substrate is lactate [ 164 – 166 ]. lncRNAs may modulate lactylation by influencing lactate availability, as shown by the overexpression of lncRNA H19, which promotes glycolysis and histone lactylation in endometriosis [ 167 ]. Understanding the interplay between lncRNAs and lactylation could uncover novel therapeutic opportunities. Inhibiting lactylation or targeting lactate production in tumors may disrupt lncRNA-mediated oncogenesis, offering promising avenues for metabolic therapy or epigenetic drug development. Furthermore, lncRNAs are increasingly being explored as therapeutic targets for manipulating lactylation in cancer treatment. Palmitoylation is a PTM in mammalian cells where a palmitate moiety is covalently attached to internal cysteine residues of target proteins through a thioester bond. This process is catalyzed by 23 members of the Asp-His-His-Cys (DHHC) family of palmitoyl S-acyltransferases, while the removal of palmitate is mediated by serine hydrolases such as acyl-protein thioesterases (APTs) [ 168 ]. By attaching a 16-carbon palmitoyl group to cysteine residues, palmitoylation influences protein structure, function, and subcellular localization, enhancing membrane association and regulating critical biological processes such as protein signaling and trafficking [ 169 , 170 ]. Dysregulation of palmitoylation has been implicated in tumorigenesis, where it modulates the activity of key oncogenes and tumor suppressors, contributing to the development and progression of various cancers [ 168 ]. Emerging evidence highlights the role of lncRNAs as regulators of palmitoylation in cancer, influencing tumor progression by modulating palmitoylation dynamics. For instance, Z. Shi et al. demonstrated that the lncRNA DUXAP8, which is highly expressed in liver cancer, promotes the palmitoylation of SLC7A11 and prevents its lysosomal degradation. This mechanism inhibits ferroptosis and contributes to resistance against sorafenib, a common treatment for HCC [ 143 ]. Similarly, C. Sun et al. reported that PVT1, upregulated in pancreatic cancer, facilitates the palmitoylation of YKT6. This modification enhances the transport, docking, and fusion of multivesicular bodies (MVBs) with the plasma membrane, promoting exosome secretion and supporting tumor progression [ 171 ]. These findings underscore the critical role of lncRNA-mediated palmitoylation in cancer progression and suggest that targeting these regulatory mechanisms could provide novel therapeutic strategies. Succinylation, a PTM that adds succinyl groups to lysine residues, plays a critical role in regulating the function of cancer-associated proteins and driving tumor progression [ 172 , 173 ]. For instance, 3-ketoacid coenzyme A transferase 1 (OXCT1), a lysine succinyltransferase, inhibits the proteolytic activity of lactamase beta (LACTB) by mediating its succinylation. This modification increases mitochondrial membrane potential and respiration, ultimately promoting HCC progression [ 174 ]. Similarly, under conditions of glutamine deprivation, the interaction between SIRT5 and mitochondrial malic enzyme 2 (ME2) is enhanced, leading to the desuccinylation of ME2. This activation of ME2 boosts mitochondrial respiration, enabling cells to adapt to glutamine deprivation and supporting CRC proliferation and tumorigenesis [ 175 ]. Emerging evidence indicates that lncRNAs play a pivotal role in regulating succinylation in cancer. For example, the lncRNA GLTC acts as a binding partner of lactate dehydrogenase A (LDHA), promoting its succinylation at lysine 155 (K155) by competitively inhibiting the interaction between SIRT5 and LDHA. This regulation enhances LDHA enzymatic activity, contributing to PTC progression and the development of radioiodine resistance [ 145 ]. Additionally, S. M. Zhang et al. have identified succinylation-related lncRNA signatures as potential prognostic markers, further underscoring the importance of lncRNAs in this regulatory process [ 176 ]. As a newly identified PTM, crotonylation has been found to play a significant role in various malignant cancers [ 177 ]. In glioblastoma stem cells, lysine metabolic reprogramming and the consequent production of crotonyl coenzyme A increase overall cellular crotonylation levels, with a particular impact on histone H4 crotonylation [ 178 ]. This histone modification influences H3K27ac and H3K9me3, thereby affecting interferon signaling and CD8 + T-cell infiltration, ultimately driving tumor growth [ 178 ]. In BRCA, hypoxic conditions lead to reduced PGK1 crotonylation mediated by ECHS1. This reduction enhances glycolysis and inhibits mitochondrial pyruvate metabolism, thereby promoting malignant progression [ 179 ]. Furthermore, recent research has revealed a link between lncRNAs and crotonylation. For instance, LINC00922 was shown to induce SIRT3 activity, which upregulates H3K27 crotonylation at the ETS1 promoter, facilitating CRC metastasis [ 144 ]. These findings suggest that crotonylation is a critical modification influencing malignant progression and highlight lncRNAs as potential key regulators of crotonylation.

Over the past two decades, extensive research has demonstrated that abnormal PTMs, including phosphorylation, ubiquitination, and acetylation, play critical roles in regulating protein function and tumorigenesis. Owing to their reversible and dynamic nature, aberrant PTMs have become attractive targets in precision oncology, offering novel therapeutic opportunities for cancer treatment. Despite substantial progress in PTM-related cancer research, significant challenges remain in translating these findings into clinical applications. Therefore, the development of innovative therapeutic strategies to improve the efficacy and specificity of PTM-targeted therapies is urgently needed. With advances in transcriptome sequencing technologies, increasing evidence has linked lncRNAs to the regulation of gene expression during tumor initiation and progression, particularly through their involvement in PTM networks. The lncRNA mediated PTM axis provides novel mechanistic insights into cancer biology. Notably, preclinical studies suggest that targeting lncRNA-mediated PTMs may reverse aberrant modifications and enhance the efficacy of conventional anticancer therapies. Thus, lncRNAs may serve as valuable adjunctive targets in cancer treatment. Integrating lncRNA-based interventions with standard therapies could help overcome drug resistance and improve therapeutic outcomes. However, the precise mechanisms of lncRNA-mediated PTM regulation remain incompletely understood and require further investigation before clinical translation can be fully realized.

Proteins, as essential biological molecules, undergo a wide range of post-translational modifications (PTMs) [ 1 ]. To date, more than 600 types of PTMs have been identified. Among them, phosphorylation, methylation, acetylation, ubiquitination, and glycosylation represent the most prevalent forms. In addition, a growing number of novel acylations, such as succinylation, crotonylation, 2-hydroxyisobutyrylation, and lactylation, have recently emerged as key regulatory marks and have drawn increasing attention for their roles in cellular signaling and cancer biology [ 2 , 3 ]. These modifications profoundly influence protein function by regulating enzyme activity, protein stability, subcellular localization, and molecular interactions [ 2 ]. Aberrant PTMs are strongly associated with cancer hallmarks, including autonomous growth signaling, sustained angiogenesis, metabolic reprogramming, and genomic instability [ 4 ]. Consequently, targeting aberrant PTMs has emerged as a central experimental and clinical strategy in cancer therapy. For instance, the proteasome inhibitor bortezomib stabilizes tumor suppressors such as p53 and p21, thereby inducing apoptosis and inhibiting cancer cell proliferation [ 5 , 6 ]. Furthermore, bortezomib disrupts the phosphorylation of epidermal growth factor receptor (EGFR), a tyrosine kinase critical to multiple malignancies [ 7 , 8 ]. Inhibiting EGFR phosphorylation has emerged as a pivotal approach to suppressing cancer cell growth and angiogenesis [ 9 , 10 ]. Thus, dysregulated PTMs represent promising but still evolving therapeutic targets for combating cancer progression. Advances in transcriptomic technologies have shed light on the regulatory roles of non-coding RNAs (ncRNAs), particularly their involvement in cancer. Among them, long non-coding RNAs (lncRNAs) have been identified as key regulators of gene expression, influencing both physiological and pathological processes [ 11 , 12 ]. Recent studies have highlighted lncRNAs as critical modulators of PTMs, with the ability to affect oncogene and tumor suppressor activity [ 13 , 14 ]. This review synthesizes the latest insights into lncRNA-mediated PTMs in cancer progression, with a particular focus on their potential roles in modulating therapeutic resistance, although their precise mechanisms remain incompletely understood.

Enzymes involved in PTMs, including protein kinases, phosphatases, methyltransferases, and ubiquitin ligases, have emerged as crucial therapeutic targets in oncology [ 180 – 182 ]. For instance, bortezomib, a proteasome inhibitor targeting the ubiquitin-proteasome system, induces apoptosis by stabilizing pro-apoptotic proteins and is a frontline treatment for multiple myeloma [ 180 ]. Monoclonal antibodies targeting EGFR block downstream oncogenic signaling pathways, thereby suppressing tumor growth [ 181 ]. Similarly, tyrosine kinase inhibitors such as Bcr-Abl inhibitors suppress phosphorylation cascades and are essential in the treatment of leukemia [ 182 ]. However, the clinical application of these agents is frequently limited by the emergence of drug resistance, off-target effects, and systemic toxicity. These limitations underscore the urgent need for novel therapeutic strategies with improved specificity and efficacy. Recent evidence suggests that lncRNAs play critical roles in regulating PTMs, particularly in the context of therapy resistance. In glioma, J. Yin et al. reported that LINC00839 acts as a molecular scaffold facilitating β-catenin phosphorylation via c-Src kinase, enhancing glioma stem cell (GSC) proliferation and resistance to radiotherapy [ 183 ]. Similarly, in nasopharyngeal carcinoma (NPC), LINC00173 binds to checkpoint kinase 2 (CHK2), impeding radiation-induced CHK2 phosphorylation and attenuating activation of the p53 pathway, thus promoting radioresistance and apoptosis evasion [ 184 ]. This mechanism not only promotes radioresistance but also inhibits apoptosis in NPC cells, enabling tumor survival under radiotherapy. In chemotherapy resistance, lncRNAs also function through PTM-dependent mechanisms. For example, B. Zhang et al. reported that lncRNA PCBP1-AS1 acts as a molecular scaffold that stabilizes the USP22-AR/AR-v7 complex, inhibiting AR ubiquitination and driving enzalutamide resistance in castration-resistant prostate cancer (CRPC) [ 185 ]. Similarly, lncRNA AC092894.1 has been shown to act as a scaffold linking AR with USP3, promoting AR deubiquitination and enhancing resistance to oxaliplatin in CRC [ 186 ]. These findings underscore the close association between lncRNA-mediated AR ubiquitination regulation and the development of drug resistance. Moreover, several lncRNAs have been implicated in resistance to other chemotherapeutic agents. MIR4435-2HG contributes to ceritinib resistance by modulating phosphorylation of mTOR, 70S6K, and 4EBP1 [ 187 ]. lncRNA CCHE1 enhances LDHA phosphorylation and activity by acting as a scaffold to promote the interaction between LDHA and fibroblast growth factor receptor 1 (FGFR1), contributing to chemotherapy resistance in melanoma [ 188 ]. In BRCA, lncRNA EILA, upregulated in CDK4/6 inhibitor (CDK4/6i)-resistant cells, promotes resistance by stabilizing cyclin E1 protein. Silencing EILA reduces cyclin E1 levels and restores sensitivity to CDK4/6 inhibitors both in vitro and in vivo [ 189 ]. Conversely, some lncRNAs may sensitize tumors to therapy. Increased levels of lncRNA PPT-1 enhance sensitivity to the SUMOylation inhibitor TAK-981 by promoting the ubiquitination and degradation of the tumor suppressor complex 2 (TSC2), increasing treatment sensitivity [ 190 ]. In conclusion, lncRNAs serve as pivotal modulators of PTMs that contribute to therapeutic resistance across diverse cancers. Through interactions with kinases, phosphatases, ubiquitin ligases, and other PTM enzymes, lncRNAs influence the stability, activity, and localization of key signaling proteins. Targeting lncRNA-mediated PTM pathways may offer novel approaches to overcome resistance in cancer therapy. However, more mechanistic insights, context-specific analyses, and clinical validation are essential to translate these findings into therapeutic applications.