The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer.

YAP is crucial for tumor cell survival, governing cell proliferation and influencing tumor immune and inflammatory states [ 233 , 234 , 235 , 236 , 237 , 238 ]. In the Hippo signaling pathway, O‐GlcNAc transferase‐induced O‐GlcNAcylation of YAP disrupts its interaction with the upstream kinase LATS1, preventing phosphorylation and activating its transcriptional activity [ 239 ]. Furthermore, in non‐Hippo pathway‐dependent YAP activation, RASSF1A expression regulates TGF‐β‐induced YAP1/SMAD2 interaction, exerting a cancer‐inhibiting effect [ 240 ]. Mechanical sensing signals activate the YAP–TAZ complex, modulate disabled homolog 2, mitogen‐responsive phosphoprotein in macrophages, and regulate integrin circulation in the three‐dimensional tumor tissue matrix, impacting extracellular matrix remodeling and metastasis [ 241 ]. Leukemia inhibitory factor receptor alpha inhibits YAP expression to hinder tumor metastasis [ 242 ]. YAP activation in Tregs enhances TGF‐β/SMAD expression, contributing to antitumor immune function [ 243 ]. YAP, functioning as an oncogene, has the potential to drive cell proliferation by modulating cell cycle progression, cellular senescence, and autophagy. This, in turn, can trigger angiogenesis and the onset of EMT, ultimately culminating in the development of the characteristic pathological morphology associated with tumors. Once YAP binds to the TEAD transcription factor, it is capable of facilitating the expression of cyclin. This, in turn, fuels the proliferation of tumor cells and enables them to perpetuate division [ 244 , 245 ]. YAP can also sustain the continuous proliferation of tumor cells by suppressing cell senescence‐associated signaling pathways [ 246 , 247 ]. Additionally, YAP can promote autophagy through its interaction with the promoter regions of autophagy‐related genes to modulate crucial proteins within the autophagy signaling pathway [ 248 , 249 , 250 , 251 ]. YAP can also activate the expression of the vascular endothelial growth factor (VEGF) gene, spurring the proliferation and migration of endothelial cells and the formation of vascular lumens. This vascular facilitation paves the way for tumor cells to infiltrate the bloodstream and embark on further distant metastasis [ 252 , 253 ]. YAP can also induce EMT in tumor cells and drive the EMT process by activating certain EMT‐related transcription factors [ 254 ]. Overall, YAP assumes a significant role in the nascent stage of tumor cell metastasis and augments the migratory and invasive capabilities of these cells. Within the tumor microenvironment (TME), YAP exerts multiple immunosuppressive effects. It can suppress the expression of crucial immune‐activating molecules. This manipulation relegates T cells to a state of immune exhaustion, consequently undermining their antitumor immune response [ 255 , 256 ]. Additionally, YAP‐activated Tregs secrete inhibitory cytokines like IL‐10 and TGF‐β, which impede the antitumor activities of other immune cells and foster an immunosuppressive milieu conducive to tumor cell survival [ 257 , 258 , 259 ]. Moreover, YAP can upregulate the expression of certain glycolytic‐related genes. By doing so, it facilitates the preferential uptake and utilization of glucose by tumor cells, thereby sustaining their growth and proliferation [ 260 , 261 , 262 ]. Such an interaction further underlines the intimate nexus between YAP and TME metabolism, highlighting the complex web of molecular crossovers that underpin tumor progression and the need for comprehensive strategies to target YAP and its associated pathways in cancer treatment. Inflammation emerges as a potent driver for YAP activation, potentially promoting tumorigenesis. Once activated in an inflammatory environment, YAP interacts with cyclin, initiating uncontrolled cell proliferation [ 263 ]. This unchecked proliferation sets the stage for the accumulation of genetic mutations in cells, increasing the likelihood of tumorigenesis. YAP also boosts the production of antiapoptotic proteins, impeding apoptosis and potentially paving the way for cellular transition into tumor cells [ 264 , 265 ]. Within inflammatory sites, YAP induces the expression of VEGF, promoting the formation of new blood vessels [ 253 , 266 ]. These vascular networks provide essential nutrients and oxygen to tumor cells, aiding their dissemination through the bloodstream and subsequent metastasis. Furthermore, YAP activation in tumor cells prompts the secretion of various inflammatory mediators. Elevated YAP levels are associated with increased secretion of these mediators [ 6 , 267 , 268 ], attracting immune cells to form inflammatory hotspots within the TME. YAP also stimulates fibroblasts to release collagen and other extracellular matrix components, altering the migration and function of immune cells and other cell types [ 269 , 270 ]. This perpetuates the inflammatory response, creating a feedback loop between inflammation and tumorigenesis. Additionally, tumor cells utilize YAP to control exosome, releasing inflammatory mediators and signaling molecules to neighboring cells [ 271 , 272 ]. This process either triggers or sustains an inflammatory reaction that fosters tumor growth and advancement. The intricate interplay involving YAP, inflammation, and tumorigenesis deepens our comprehension of cancer pathophysiology and unveils promising therapeutic pathways for future investigation. Head and neck tumors, predominantly thyroid, nasopharyngeal, oral, laryngeal, and sinus cancers. Variations in anatomical location, pathological types, and mechanisms among these tumors result in diverse treatment approaches [ 273 , 274 , 275 ]. Nasopharyngeal cancer, for instance, responds well to radiotherapy [ 276 ], while laryngeal, oral, and sinus cancers typically require a combination of surgical intervention, postoperative radiotherapy, and chemotherapy for effective management [ 277 , 278 , 279 , 280 ]. These distinct therapeutic strategies highlight the importance of tailored treatment regimens based on the specific molecular pathologic mechanisms of each head and neck malignancy. YAP1 is a key promoter of head and neck squamous cell carcinoma [ 281 ]. The interaction between actin like 6A and p63 activates Hippo–YAP via WW domain containing 1, contributing to the promotion of head and neck squamous cell carcinoma [ 282 ]. Nasopharyngeal carcinoma is a malignant epithelial tumor that originates from the nasopharyngeal mucosa [ 283 , 284 , 285 ]. Recent studies have identified Epstein–Barr virus infection and smoking as contributing factors to its pathogenesis. Typically, nasopharyngeal cancer presents with early lymph node enlargement in the neck and epistaxis. While radiotherapy remains the primary treatment for nasopharyngeal carcinoma, surgery has increasingly become a viable option for recurrent cases in recent years [ 286 , 287 ]. YAP plays a crucial role in the development of nasopharyngeal carcinoma. circRILPL1 inhibits the LATS1–YAP kinase cascade in the Hippo pathway by binding to and activating Rho‐associated coiled‐coil containing protein kinase 1 (ROCK1), leading to reduced YAP phosphorylation [ 288 ]. Cytoplasmic leukemia inhibitory factor promotes vascular dissemination and local invasion of nasopharyngeal carcinoma by modulating the YAP1–focal adhesion kinase (FAK)/paxillin signaling pathway [ 289 ] (Figure S4A ). Thyroid cancer primarily stems from malignant tumors of the thyroid follicular or parafollicular epithelium. The most common type is papillary carcinoma, with undifferentiated carcinoma carrying the poorest prognosis [ 290 , 291 ]. Initially asymptomatic, thyroid cancer can progress to cause breathing difficulties, hoarseness, and cervical lymph node metastasis in advanced stages [ 292 , 293 ]. YAP plays a pivotal role in the development of thyroid cancer. Ubiquitin carboxyl terminal hydrolase L3 stabilizes YAP through deubiquitinating activity, enhancing anaplastic thyroid cancer progression, stemness, metastasis, and increasing cell sensitivity to chemotherapy [ 294 ]. Neurofibromatosis type 2 (NF2)/merlin inactivation boosts RAS protein activation by enhancing YAP/TEAD activity [ 295 ]. YAP–TEAD1 induces platelet‐derived growth factor‐BB (PDGF‐BB) transcription, while PDGF‐BB, via its receptor PDGFR, stabilizes YAP and facilitates YAP nuclear translocation [ 296 ] (Figure S4A ). Malignant peripheral nerve sheath tumors originate from peripheral nerve Schwann cells [ 297 , 298 ]. Their location varies, and symptoms typically manifest as localized masses, with potential for metastases to distant lymph nodes and the bloodstream [ 299 ]. Excessive TAZ/YAP activity in Schwann cells due to LATS1/2 deletion in the Hippo pathway could lead to the development of malignant peripheral nerve sheath tumors [ 300 , 301 , 302 ] (Figure S4B ). Melanoma, a malignant tumor derived from melanocytes, can arise in various locations including the skin (limbs, toes), mucous membranes (nasal and oral cavities, digestive tract), and the uvea of the eye [ 303 , 304 ]. Mutations within melanoma cells trigger extensive proliferation, fostering the spread of cancer cells and their infiltration into organs. Historically, surgical resection has been the cornerstone of melanoma treatment, often complemented by therapies like immunotherapy [ 305 , 306 ]. Recent studies have elucidated the significant involvement of YAP in both the development and progression of melanoma, shedding light on potential therapeutic targets for this aggressive cancer. The YAP–TEAD interaction is crucial in uveal melanoma [ 307 ]. Gαq facilitates YAP‐dependent growth in uveal melanoma cells [ 308 ]. Guanine nucleotide‐binding protein, Q polypeptide (GNAQ) activates YAP via FAK, driving uveal melanoma progression [ 309 , 310 , 311 ]. The β‐catenin–YAP signaling axis activates stromal fibroblasts, fostering melanoma progression [ 312 ] (Figure S4C ). Breast cancer predominantly arises from mammary epithelial cells and is intricately linked to female hormones [ 313 , 314 ]. This prevalent malignancy in women is stratified into noninvasive and invasive subtypes, with noninvasive cases generally exhibiting a more favorable prognosis compared with the metastatic potential of invasive forms. Early manifestations such as breast masses, nipple discharge, and enlarged axillary lymph nodes mark the initial stages of the disease, which can progress to systemic metastasis over time [ 315 , 316 ]. Treatment modalities for breast cancer typically encompass a multidisciplinary approach involving surgery, chemotherapy, and endocrine therapy, tailored to individual patient needs [ 317 , 318 , 319 ]. Recent research has unveiled the pivotal role of YAP in the pathogenesis of breast cancer, shedding light on potential therapeutic targets and avenues for further exploration in the quest to enhance treatment efficacy and patient outcomes. In the realm of cancer research, lncRNA SNHG9 acts by inhibiting the Hippo pathway through LATS1 [ 320 ], while ROR1–human epidermal growth factor receptor 3 (HER3)–lncRNA LLGL2–MAYA–NOP2/Sun RNA methyltransferase 6 is involved in regulating the Hippo–YAP pathway to control bone metastasis in breast cancer [ 321 ]. Moreover, seven in absentia homolog 2 inhibits LATS2 to stimulate YAP [ 322 ], and LATS1/2 maintains estrogen receptor alpha (Erα) expression by inhibiting YAP/TAZ, thereby promoting the growth of ERα+ breast cancer cells. YAP1 and TEAD4 can also serve as ERα cofactors to further boost the growth of ERα(+) breast cancer [ 323 , 324 ]. Additionally, PA directly interacts with Hippo components LATS and NF2, disrupting the formation of the LSAT–MOB1 complex and NF2‐mediated translocation and activation of LATS membrane, ultimately leading to the activation of YAP [ 325 ]. Notably, there are instances where direct stimulation of YAP occurs independently of the Hippo pathway in breast cancer. TNF‐α in breast cancer is known to promote IκB kinase‐mediated phosphorylation and activation of YAP, with YAP/TEAD and p65 proteins working synergistically to regulate hexokinase 2 expression and promote macrophage migration [ 326 ]. Loss of cerebral cavernous malformation 3 leads to YAP/TAZ activation [ 327 ], and FAT1 deletion significantly increases cyclin‐dependent kinase 6 through YAP and TAZ transcription factors [ 245 ]. The SREBP/mevalonate pathway is instrumental in promoting YAP/TAZ activation [ 328 ]. Furthermore, YAP is involved in regulating protein levels in anillin (ANLN), diaphanous‐related formin 3, and myosin light chain 9 to maintain the phenotype of breast cancer‐associated fibroblasts [ 20 ]. YAP's ability to promote amphiregulin contributes to cell proliferation and migration [ 329 ], and lncRNA MALAT1 binds to TEAD, preventing it from binding to its coactivator YAP and the target gene promoter [ 330 ]. Last, MYC enhances AMPK and inhibits YAP/TAZ activity in breast tumors [ 331 ] (Figure S4D ). Gastric cancer, a malignancy originating in the stomach lining cells, typically progresses slowly with symptoms manifesting prominently only in advanced stages [ 332 , 333 ]. The development of this cancer involves a complex interplay of genetic and environmental factors, including Helicobacter pylori infection, dietary patterns, smoking, and genetic predisposition. Mechanistically, gastric cancer onset is intricately linked to gene mutations, inflammatory responses, DNA damage, and metabolic irregularities that impede cell growth and apoptosis [ 334 , 335 , 336 , 337 , 338 ]. Treatment strategies for gastric cancer vary based on tumor stage and patient health. Surgery stands as the primary intervention for early‐stage cases, aiming at complete tumor removal. In advanced stages, a multidisciplinary approach combining surgery with chemotherapy and radiotherapy is commonly employed to alleviate symptoms, manage disease progression, and enhance patient survival rates. The evolving landscape of targeted therapies presents promising avenues for improved outcomes in gastric cancer management, offering novel treatment prospects for patients. The overexpression of YAP1 intensifies the aggressive behavior of gastric cancer cells [ 339 ]. In the context of the Hippo pathway in gastric cancer, Striatin 3 facilitates MST1/2 dephosphorylation through protein phosphatase 2A (PP2A), activating YAP and driving gastric cancer progression [ 340 ]. Moreover, MST4‐mediated YAP phospho–Thr83 signaling modulates YAP phospho–Ser127 signaling to suppress YAP activation in gastric cancer [ 341 ]. Independent activation of YAP, separate from the Hippo pathway, also plays a pivotal role in advancing gastric cancer. YAP and β‐catenin work synergistically to propel gastric cancer development through their physical interactions [ 342 ]. The claudin 18–Rho GTPase activating protein 26 fusion, an acquired DGC oncogene, accelerates gastric cancer growth by activating YAP signaling [ 343 ]. IRF3 enhances YAP expression, facilitating YAP–TEAD4 binding to promote gastric cancer development [ 344 ]. The rigidity of the extracellular matrix in gastric cancer dynamically influences DNA methylation in the YAP promoter region [ 345 ]. Alanyl‐tRNA synthetase 1 senses intracellular lactic acid, translocating to the nucleus to activate the YAP–TEAD complex, stimulating gastric cancer cell proliferation [ 346 ]. YAP/TAZ drives the differentiation of CD54+ tumor‐specific neutrophils in gastric cancer, fueling tumor progression [ 347 ]. Additionally, miR‐15a and miR‐16‐1 suppress gastric adenocarcinoma by reducing YAP levels [ 348 ]. Vestigial‐like protein 4 (VGLL4) inhibits YAP activity by competitively binding TEADs, hindering the advancement of gastric cancer [ 349 ] (Figure  5A ). Molecular mechanism of YAP in gastric cancer, liver cancer and cholangiocarcinoma. (A) Mechanism of YAP in gastric cancer. (B) Mechanism of YAP in liver cancer. (C) Mechanism of YAP in melanoma. (D) Mechanism of YAP in cholangiocarcinoma. AKT, protein kinase B; AXIN1, axonemal assembly protein 1; BMI1, B lymphoma Mo‐MLV insertion region 1; c‐Myc, cellular myelocytomatosis oncogene; CD44, cluster of differentiation 44; CREB, cAMP response element binding protein; CSN6, COP9 signalosome 6; DLG1, discs large homolog 1; DNMT3A, DNA methyltransferase 3 alpha; Fbxw7, F‐box and WD repeat domain‐containing 7; Glu, glutamic acid; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HIF‐1α, hypoxia‐inducible factor‐1α; HMGCS1, 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 1; HNF4α, hepatocyte nuclear factor 4 alpha; I‐DDR1, discoidin domain receptor 1; IL, interleukin; ILC2, type 2 innate lymphoid cells; IRF3, interferon regulatory factor 3; IRS2, insulin receptor substrate; Jag1, Jagged1; LATS1, large tumor suppressor homolog 1; MCP1, monocyte chemoattractant protein 1; MST1, mammalian sterile 20‐like protein kinase 1; MST4, mammalian sterile 20‐like protein kinase 4; mTORC1, mechanistic target of rapamycin complex 1; Nogo‐B, reticulon 4B; NUAK2, NUAK family kinase 2; PP2A, protein phosphatase 2A; PP2AA, protein phosphatase 2A; PLD1, phospholipase D1; RACGAP1, Rac GTPase‐activating protein 1; RNF214, ring finger protein 214; SDHA/B, succinate dehydrogenase complex subunit A/B; Skp2, S‐phase kinase‐associated protein2; SLC38A1, solute carrier family 38 member 1; SLC7A5, solute carrier family 7 member 5; SMAD7, mothers against decapentaplegic homolog 7; Sox9, SRY‐related HMG‐box 9 protein; SPTAN1, spectrin alpha nonerythrocytic 1; STRN3, striatin 3; TAZ, transcriptional coactivator with PDZ‐binding motif; TBX3, T‐box transcription factor 3; TEADs, TEA domain transcription factors; TRIB2, tripartite motif protein VGLL4, vestigial like family member 4; Wnt, wingless‐related integration site; WWC, WW domain containing cytoskeleton regulatory protein 1; YAP, Yes‐associated protein; ZNF191, zinc finger protein 191. The figure is created by Figdraw. Liver cancer, a prevalent malignant tumor globally, arises from liver cells, with hepatocellular carcinoma (HCC) and cholangiocarcinoma as typical forms [ 172 , 350 ]. Its occurrence is frequently linked to cirrhosis, hepatitis B virus infection, alcoholism, liver steatosis, and genetic factors [ 351 , 352 ]. Treatment avenues encompass surgical resection, liver transplantation, chemotherapy, radiotherapy, and targeted therapy. Surgical resection is the primary choice for early‐stage liver cancer, while liver transplantation emerges as a viable option for advanced cases. Chemotherapy and radiotherapy play crucial roles in symptom alleviation, disease management, and survival extension [ 353 , 354 ]. The pathogenesis of liver cancer remains intricate and not yet fully elucidated. YAP and TAZ function as universally activated transcriptional regulators in liver tumors [ 4 , 267 , 355 ‐ 365 ]. lncRNA uc.134 impedes HCC progression by inhibiting cullin 4A‐mediated LATS1 ubiquitination and enhancing YAP(S127) phosphorylation [ 366 ]. The spectrin alpha, nonerythrocytic 1/NUMB axis restrains liver cancer cell growth through Hippo signaling [ 367 ]. Deletion of WW and C2 domain proteins hinders LATS1 phosphorylation, fostering YAP activation in the Hippo pathway, resulting in liver tissue overgrowth, inflammation, fibrosis, and liver cancer formation [ 368 ]. Chronic inflammation dampens epithelial splicing regulatory protein 2 expression in hepatocytes, impeding Hippo pathway activation, elevating downstream YAP/TAZ activity, and fostering hepatobiliary carcinoma in the presence of chronic liver injury [ 369 ]. Rac GTPase activating protein 1 diminishes Hippo activity, activating the YAP pathway to spur cell division and promote liver cancer cell proliferation [ 370 ]. Collagen I–DDR1 interacts with CD44, facilitating PP2A, catalytic subunit, alpha isoform (PP2AA) recruitment to MST1, counteracting Hippo signaling, activating YAP, and advancing HCC progression [ 371 ]. The Hippo signal curbs macrophage infiltration during TME formation by suppressing YAP‐dependent monocyte chemoattractant protein 1 expression, restraining liver cancer cell growth [ 372 ]. Hippo–yap signaling deters cell polyploidy and liver tumorigenesis via S‐phase kinase‐associated protein 2 [ 373 ]. Mst1/2 curtails Yap1 activity to impede liver tumor development [ 374 ]. Notably, activation of YAP independent of hippo pathway has also been commonly reported in liver cancer. Hepatitis B virus X protein spurs liver cancer cell growth in a CREB‐dependent manner through YAP [ 375 ]. TAZ expression in human liver tumors attracts numerous myeloid cells to infiltrate the liver, secreting proinflammatory cytokines via a TEAD‐dependent mechanism [ 376 ]. T‐box 3 inactivation of phospholipase D1 curbs YAP/TAZ activation, thwarting HCC progression [ 377 ]. F‐box and WD repeat domain‐containing 7 modulates HCC progression regulated by YAP through YAP ubiquitination and proteasome degradation [ 378 ]. The CD36–Nogo‐B–YAP pathway reshapes oxidized low‐density lipoprotein metabolism, inducing HCC linked to nonalcoholic fatty liver disease [ 361 ]. SMAD7 participates in liver cancer by activating the YAP/NOTCH signaling cascade, triggering bile duct cell signals and epithelial mesenchymal transformation [ 379 ]. HMGB1 induces YAP–HIF‐1α complex‐dependent aerobic glycolysis, fueling liver tumor progression [ 380 ]. SRY‐box 9 (Sox9) signaling proves essential for YAP to drive hepatic progenitor cell differentiation into biliary epithelial cells, with Sox9 deletion elevating YAP activity, fostering more aggressive HCC [ 18 , 381 ]. COP9 signalosome subunit 6 stabilizes 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 1 (HMGCS1) by counteracting speckle‐type POZ protein ubiquitin ligase, activating YAP1 to spur liver tumor growth [ 382 ]. Cholesterol boosts TAZ and TEAD2 interactions, promoting ANLN and kinesin family member 23‐mediated hepatocellular tumorigenesis [ 383 ]. β‐Catenin and Yap1 collaborate to propel tumor progression in hepatoblastoma [ 384 ]. Ring finger protein 214 triggers nonproteolytic ubiquitination of conserved lysine residues of TEADs, strengthening TEADs and YAP interaction, advancing liver cancer progression [ 385 ]. Axin 1 binds to YAP/TAZ in human HCC cells, regulating YAP/TAZ stability [ 386 ]. Succinate dehydrogenase complex flavoprotein subunit A/B reduction averts proteasome degradation of YAP/TAZ by modulating cullin1 neddylation, boosting HCC proliferation [ 387 ]. NUAK family kinase 2 (NUAK2) activates YAP by enhancing actin polymerization and myosin activity, fostering liver cancer cell proliferation [ 388 ]. Notch signaling spurs YAP/TAZ activation, while Wnt/β‐catenin signaling activation drives HCC formation [ 389 ]. HNF4α directly binds to TEAD4, competing with YAP1 for TEAD4, stalling liver cancer cell proliferation [ 390 ]. CREB bolsters YAP transcription by binding to the −608/−439 region of the YAP promoter, with YAP enhancing CREB protein stabilization by interacting with mitogen‐activated protein kinase (MAPK)14/p38 and β‐transduction repeats of BTRC, fueling liver cancer progression [ 391 ]. TRIB2 boosts stable YAP expression by interacting with beta‐transducin repeat‐containing protein (βTrCP) ubiquitin ligase [ 392 ]. The hepatitis B surface antigen (HBsAg)–YAP–B lymphoma Mo–MLV insertion region 1 homolog (BMI1) axis propels hepatitis B virus‐associated proliferative HCC progression [ 393 ]. Zinc finger protein 191 curtails YAP activation by upregulating discs large homolog 1, thwarting HCC metastasis [ 394 ]. Additionally, YAP1 directly heightens glutamine synthetase expression and activity, enhancing glutamine homeostasis and nitrogen isotope enrichment during new purine and pyrimidine biosynthesis, fostering liver tumorigenesis [ 395 ]. YAP1/TAZ regulates amino acid metabolism by upregulating olute carrier family 38 member 1 and SLC7A5, activating mechanistic target of rapamycin complex 1 to spur liver cancer cell proliferation [ 396 ]. YAP‐1 acts as the core mediator of fibrotic integrin β‐1 signaling, playing a crucial role in liver fibrosis [ 397 ]. YAP/TAZ activation amplifies AKT signaling by upregulating insulin receptor substrate 2 expression, promoting cancer progression [ 398 ]. YAP boosts Jagged 1 expression to activate Notch signaling, driving HCC proliferation [ 399 ] (Figure  5B ). Cholangiocarcinoma is a malignancy that originates from cells within the bile duct. It is typically classified into two primary types: intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma [ 400 , 401 ]. The development of this cancer is intricate, involving genetic factors, inflammation, gallstones, cholangitis, biliary diseases, and parasitic infections. Common treatment options encompass surgical resection, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Surgical resection is considered the primary treatment for early‐stage cholangiocarcinoma, particularly for tumors that are localized within the ductal system [ 402 , 403 , 404 ]. Additionally, YAP plays a pivotal role in the pathogenesis of cholangiocarcinoma. In contrast to the conventional Hippo pathway, DNMT3A interacts with YAP/TAZ, leading to the transcriptional silencing of CDH1, thereby promoting gallbladder cancer metastasis [ 405 ]. The persistent activation of AKT and YAP triggers IL‐33/ILC2/IL‐13 pathways, fostering hepatic metastasis of cholangiocarcinoma [ 406 ]. YAP stimulates cholangiocarcinoma progression through TEAD‐dependent transcriptional activation and beta‐catenin interaction [ 407 ] (Figure  5C ). Pancreatic cancer, arising from the pancreatic ductal epithelium and acinar cells, is characterized by a poor prognosis and typically manifests in either the pancreatic head or tail [ 408 , 409 ]. The development of pancreatic cancer involves a complex interplay of genetic factors, inflammation, pancreatic disorders, obesity, smoking, and diabetes [ 410 ]. Surgical resection stands out as the primary approach for managing early‐stage pancreatic cancer, particularly in cases of locally resectable tumors [ 411 ]. Chemotherapy and radiotherapy frequently complement surgical interventions, serving as adjuvant therapies administered pre‐ or postoperatively to diminish tumor burden, regulate disease progression, and enhance surgical outcomes [ 412 , 413 , 414 ]. In pancreatic cancer, direct YAP activation can drive tumor progression. Zinc transporter 4 boosts YAP1 expression by activating miR‐373 and suppressing LATS2 [ 415 ]. TEAD/YAP collaboration fosters pancreatic cancer advancement [ 416 , 417 , 418 ]. Carcinogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) elevates JAK–STAT3 signaling via YAP1 and TAZ activation, promoting acinar to duct metaplasia and initiating pancreatic ductal adenocarcinoma progression [ 419 ]. Yap‐induced miR‐130a enhances YAP levels by targeting VGLL4 [ 420 ]. SDCBP impedes βTrCP (beta‐TRCP)‐mediated YAP1 degradation [ 421 ]. Ubiquitin‐specific peptidase 14 (USP14) facilitates K48‐linked TAZ deubiquitination, stabilizing TAZ [ 422 ]. Sul2 heightens PDGF receptor beta–YAP signaling, stimulating tumor growth and chemotherapy resistance [ 423 ]. lncRNA THAP9–AS1 amplifies YAP signaling [ 424 ]. Tamoxifen curbs myofibrogenic differentiation of pancreatic stellate cells in pancreatic cancer by deactivating YAP [ 425 ]. p53 boosts Ptpn14 expression, restraining YAP levels [ 426 , 427 ] (Figure  6A ). Molecular mechanism of YAP in pancreatic cancer, colorectal cancer, and lung cancer. (A) Mechanism of YAP in pancreatic cancer. (B) Mechanism of YAP in colorectal cancer. (C) Mechanism of YAP in lung cancer. ABHD5, abhydrolase domain containing 5; ALKBH5, AlkB homolog 5; β‐TrCP, β‐transducin repeat containing E3 ubiquitin protein ligase; Bcl‐xl, B‐cell lymphoma‐2 like protein 1, long isoform; BMF, Bcl‐2 modifying factor; c‐Met, mesenchymal–epithelial transition factor; c‐Yes, cellular Yes; CK2, casein kinase 2; DDK3, Dickkopf‐related protein 3; EGFR, epidermal growth factor receptor; ETS1, E26 transformation‐specific 1; EP4, prostaglandin E receptor 4; FOXM1, Forkhead box protein M1; HHEX, hematopoietically expressed homeobox; ISLR, immune‐signaling leucine‐rich repeat containing protein; JAK–STAT3, Janus kinase‐signal transducer and activator of transcription 3; KDM3A, lysine demethylase 3A; KRAS, kirsten rat sarcoma viral oncogene homolog; LATS1, large tumor suppressor homolog 1; Mcl1, myeloid cell leukemia sequence 1 apoptosis regulator; MEK, mitogen‐activated protein kinase kinase; MOB1, Mps one binder 1; MVA, mevalonic acid; NF‐κb, nuclear factor kappa B; PDGFRβ, platelet‐derived growth factor receptor β; PGE(2), prostaglandin E2; PP2A, protein phosphatase 2A; RASAL2, RAS protein activator like 2; REGγ, regulator of G protein signaling gamma; SDCBP, syndecan binding protein; SIK2, salt‐inducible kinase 2; SIRPγ, signal regulatory protein gamma; SLUG, Snail family zinc finger 2; SREBP2, sterol regulatory element binding protein‐2; TAZ, transcriptional coactivator with PDZ‐binding motif; TIAM1, T‐cell lymphoma invasion and metastasis inducing protein 1; USP47, ubiquitin‐specific peptidase 47; USP14, ubiquitin‐specific protease 14; VGLL4, vestigial like 4; YAP, Yes‐associated protein; YTHDF1, YTH domain family protein 1; ZIP4, Zrt‐ and Irt‐like protein 4; ZMYND8, zinc finger MYND‐type containing 8. The figure is created by Figdraw. Colorectal cancer, a malignancy arising in the epithelial cells of the colon or rectum, presents a multifaceted etiology involving genetic predisposition, dietary habits, lifestyle choices, and age [ 428 , 429 ]. Genetic susceptibility, along with family history, are factors that can significantly heighten the risk of developing this condition. The typical manifestations of colorectal cancer include changes in bowel habits, abdominal discomfort, and rectal bleeding [ 430 , 431 ]. Although surgical resection serves as the principal treatment approach for early‐stage colorectal cancer, the complex pathological characteristics of the disease present difficulties. Even with the incorporation of adjuvant therapies like postoperative radiotherapy and chemotherapy, attaining the best possible treatment outcomes still proves to be a formidable task [ 431 , 432 , 433 , 434 ]. YAP1 activation correlates with colorectal cancer progression and poor prognosis [ 192 , 435 ‐ 438 ]. In the Hippo pathway, regulator of G protein signaling gamma directly interacts with Lats1, facilitating its degradation and mutual activation of YAP and NF‐κB pathways [ 439 ]. The oncogenic transcription factor ETS proto‐oncogene 1 within stromal cells triggers the expression of immunoglobulin superfamily leucine‐rich repeat containing. This, in turn, suppresses Hippo signaling and activates YAP in epithelial cells. As a result, it promotes the regeneration of intestinal epithelial cells and contributes to tumorigenesis [ 440 ]. Ras GTPase activating protein like 2 (RASAL2) promotes colorectal cancer through the LATS2/YAP1 axis of the Hippo signaling pathway [ 441 ]. Circ‐YAP encodes YAP‐220AA, competitively binding to LATS1, leading to YAP dephosphorylation and nuclear translocation, promoting liver metastasis progression in colorectal cancer [ 442 ]. Beyond the Hippo pathway, the prostaglandin E (PGE) (2) signaling pathway enhances YAP1 expression and activity, upregulating cyclocyception 2 and prostaglandin E receptor 4 (EP4), stimulating colon cancer cell proliferation and colon tissue regeneration in colitis mice [ 443 ]. The interaction between tyrosine kinases c‐Yes and YAP fosters colon cancer recurrence [ 444 ]. Dickkopf‐related protein 3 orchestrates the coactivation of β‐catenin and YAP/TAZ [ 445 ]. Abhydrolase domain‐containing 5 deletion initiates the translocation of Dumpy homolog 30 to the nucleus, leading to the activation of SET domain‐containing 1A, which in turn facilitates the nuclear translocation of YAP. This process enhances the transcription of c‐Met, thereby promoting the stemness of colon cancer cells [ 446 ]. Casein kinase 2 facilitates hematopoietically expressed homeobox interaction with YAP/TEAD [ 447 ]. STAT3‐mediated signaling in colorectal cancer and melanoma endothelial cells boosts YAP/TAZ activity, driving angiogenesis [ 268 ]. Via the interaction between zinc finger MYND domain containing 8 and SREBP2, YAP elevates the expression of genes in the mevalonic acid pathway. This molecular process contributes to the progression of cholesterol‐related development in colorectal cancer [ 448 ]. VGLL4 targets the Tead4‐transcription factor 4 (TCF4) complex, disrupting TEAD4–TCF4 functional interaction [ 449 ]. Lysine demethylase 3A (KDM3A) [ 450 ], MAPK kinase [ 451 ] and USP47 [ 452 ] bolster YAP stability in colorectal cancer, while miR‐195‐5p inhibits YAP expression [ 453 ]. T lymphoma invasion and metastasis‐inducing protein 1 (TIAM1) hinders colorectal cancer progression by impeding YAP/TAZ interaction with TEADs [ 454 ] (Figure  6B ). Lung cancer is a malignant tumor originating from the mucous membranes or glands of the trachea and bronchus [ 455 , 456 , 457 , 458 ]. The main causes of lung cancer include smoking, air pollution, and genetic predispositions, with smoking being the primary risk factor. Lung cancer is classified into non‐small cell lung cancer and small cell lung cancer [ 459 ]. Symptoms such as coughing, blood in sputum, or hemoptysis highlight the crucial need for early screening and diagnosis to improve treatment effectiveness. Common treatments for lung cancer include surgical resection, chemotherapy, radiation, and targeted therapy. Surgical excision is commonly used for early‐stage non‐small cell lung cancer, while chemotherapy and radiation are standard options for advanced cases or as adjunctive measures before and after surgery [ 460 , 461 , 462 ]. YAP expression in small cell lung cancer impacts disease cell phenotype, intertumor, and intratumor heterogeneity [ 265 , 463 ‐ 466 ]. In lung adenocarcinoma cells, the interplay between EGFR and salt‐inducible kinase 2 within the Hippo pathway impedes the interaction between LATS1 and MST1. This process promotes the nuclear translocation of YAP and contributes to the development of resistance to tyrosine kinase inhibitors [ 467 ]. The regulatory axis of oxidative stress and CREB‐binding protein (CBP) controls MOB1–K11 acetylation, leading to the activation of LATS1 and initiation of the Hippo pathway. This activation inhibits the nuclear translocation of YAP/TAZ, thereby impeding the progression of non‐small cell lung cancer tumors [ 468 ]. SIRP gamma acts as a bridge between MST1 and PP2A, facilitating MST1 dephosphorylation and activating the Hippo/YAP pathway. This activation leads to the release of cytokines from tumor stem cells, triggers CD47 expression in lung adenocarcinoma cells, and ultimately inhibits the phagocytosis of tumor cells [ 469 ]. The N6‐methyladenosine (m(6)A) demethylase AlkB homolog 5 suppresses the growth and metastasis of non‐small cell lung cancer by decreasing YTH domain family protein 1‐mediated YAP expression and blocking miR‐107/LATS2‐mediated YAP activity [ 470 ]. Beyond the Hippo pathway, lung cancer cells survive EGFR inhibitor therapy through STAT3 and Src–YAP1 signaling activation [ 471 ]. Additionally, YAP/TEAD complex interacts with the EMT factor Snail family transcriptional repressor 2 (SLUG), which suppresses the proapoptotic factor Bcl‐2 modifying factor. This interaction restricts drug‐induced apoptosis in non‐small cell lung cancer cells [ 472 ]. The YAP/FOXM1 axis contributes to EGFR inhibitor resistance associated with EMT in lung cancer [ 19 ]. YAP suppresses squamous transdifferentiation of liver kinase B1‐deficient lung adenocarcinoma through zinc finger E‐box binding homeobox 2‐dependent DeltaNp63 [ 473 ]. YAP1 induces the expression of antiapoptotic factors myeloid cell leukemia sequence 1 (Mcl‐1) and B‐cell lymphoma‐extra large, enhancing lung cancer cell survival [ 474 ]. The YAP/TEAD pathway drives epigenome reprogramming and EMT to counteract lung cancer cell apoptosis [ 235 ] (Figure  6C ). Renal cancer, originating from the tubular epithelium of the kidney, includes different subtypes like clear cell carcinoma and papillary cell carcinoma. Among these, clear cell carcinoma is the most common subtype [ 475 , 476 ]. The exact cause of kidney cancer remains unclear, but common risk factors include smoking, obesity, high blood pressure, and genetic predisposition. Symptoms of kidney cancer may include lower back pain, hematuria, and the presence of a kidney mass. Surgical interventions like partial or total nephrectomy are the main treatment options. Targeted therapies are crucial in managing kidney cancer by focusing on specific tumor growth factors or proteins, inhibiting tumor growth and spread [ 477 , 478 , 479 ]. YAP has emerged as a crucial gene involved in the development of kidney cancer. The interaction between lncARSR and YAP hinders YAP phosphorylation by Lats1 within the Hippo pathway. This process promotes YAP nuclear translocation, enhancing the tumorigenic activity of renal cell carcinoma cells in the kidney [ 480 ]. Studies indicate that partial activation of YAP in renal cancer can occur regardless of the Hippo pathway. In clear cell renal cell carcinoma, macrophages associated with the SOX17 (low)/YAP–TEAD1/CCL5/CCR5/STAT3 axis play a role in promoting metastasis and resistance to targeted drugs [ 481 ]. The circEHD2/tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein eta/YAP/SOX9 signaling pathway accelerates the growth of clear cell renal cell carcinoma [ 482 , 483 ] (Figure  7A ). Molecular mechanism of YAP in renal cancer, bladder cancer, and prostate cancer. (A) Mechanism of YAP in renal cancer. (B) Mechanism of YAP in bladder cancer. (C) Mechanism of YAP in prostate cancer. CCL5, chemokine (C–C motif) ligand 5; CCR5, chemokine (C–C motif) receptor 5; CXCL5, chemokine (C–X–C motif) ligand 5; ERG, ETS‐related gene protein; ETV1, ETS variant transcription factor 1; JMJD2A, Jumonji domain‐containing protein 2A; LATS1, large tumor suppressor homolog 1; NUAK2, NUAK family, SNF1‐like kinase 2; PDGF‐BB, platelet‐derived growth factor subunit B dimer; PDGFR, platelet‐derived growth factor receptor; SOX9: sex‐determining region Y‐box 9; SOX17, Sex‐determining region Y‐Box 17; STAT3, signal transducer and activator of transcription 3; TEADs, TEA domain transcription factors; YAP, Yes‐associated protein; YWHAH, 14‐3‐3 protein eta. The figure is created by Figdraw. Bladder cancer, a malignancy originating in the mucous membrane of the bladder, is commonly categorized into nonmuscular invasive and muscular invasive types [ 484 , 485 , 486 ]. Smoking stands out as a primary risk factor associated with this condition. Typical symptoms of bladder cancer encompass hematuria, frequent urination, urgency to urinate, lower back pain, and the presence of blood clots in the urine. Recognized as a multifaceted disease, early detection and intervention are pivotal in enhancing patient survival rates and overall well‐being [ 487 , 488 ]. A comprehensive approach to managing bladder cancer involves a spectrum of treatments such as surgery, chemotherapy, radiotherapy, and emerging therapies [ 489 , 490 , 491 ]. The significance of YAP in bladder cancer has been highlighted, illuminating its role in the disease's development and possible therapeutic approaches. CircXRN2 inhibits bladder tumor advancement triggered by histone H3 lysine 18 lactation through the activation of the Hippo signaling pathway [ 492 ]. NUAK2 directly hinders LATS‐mediated YAP/TAZ phosphorylation, leading to YAP activation [ 493 ]. Upon YAP activation, YAP/TEAD1 enhances PDGF‐BB transcription, while PDGF‐BB, via its receptor PDGFR, stabilizes YAP and facilitates YAP nuclear translocation [ 296 ] (Figure  7B ). Prostate cancer, an epithelial malignant tumor originating in the prostate, represents a prevalent malignancy within the male urinary system [ 494 ]. Characterized by a gradual progression, the exact cause of this condition remains incompletely understood, with factors such as age, family history, ethnicity, diet, and genetic components believed to play a significant role in its development [ 495 , 496 ]. Symptoms of prostate cancer include frequent urination, urgency to urinate, and difficulties with urination. Common treatment options for prostate cancer include surgical resection, radiation therapy, chemotherapy, hormone therapy, and targeted therapy [ 497 , 498 ]. The significant role of YAP in the development of prostate cancer emphasizes its crucial involvement in disease advancement and possible therapeutic strategies. In prostate cancer, the erythroblast transformation specific‐related gene binds to the chromatin region that is also occupied by TEAD/YAP [ 499 ]. ETS variant transcription factor 1 plays a role in recruiting YAP1 to the promoter region through JMJD2A, leading to changes in histone lysine methylation in human prostate cancer cell lines. This interaction highlights the complex regulatory network involved in prostate cancer progression [ 500 ]. The YAP–TEAD complex additionally promotes the upregulation of CXCL5 in cancer cells and facilitates the recruitment of polymorphic nuclear myeloid suppressor cells, thereby advancing the progression of prostate cancer [ 501 ] (Figure  7B ).

B. Z., S. S., J. D. and F. L. contributed to drafting and editing of the manuscript. All authors have read and approved the final manuscript.

The authors have nothing to report.

In the realms of inflammatory conditions and cancer treatment, a promising targeted therapy approach revolves around suppressing the elevated expression of YAP. Given its crucial role in the Hippo pathway, strategies that directly target YAP or disrupt the interaction between YAP/TAZ and TEADs are effective ways to regulate YAP expression. Additionally, future therapeutic strategies may involve modulating YAP activation and degradation by influencing the phosphorylation of MST1/2 and LATS1/2, presenting a hopeful pathway for intervention. Blocking YAP activation presents a promising avenue for treating inflammatory conditions and represents a novel strategy for future therapeutics. Triptolide has been demonstrated to inhibit the release of inflammatory mediators and mucus secretion by targeting YAP [ 65 ]. Prostaglandin E(2) has been identified as reducing fibroblast formation in asthma by inhibiting YAP [ 70 ]. The decrease in angiokinin‐like 2 and YAP1 inhibits airway smooth muscle cell proliferation in asthma [ 81 ]. Csrp2 inhibits the transition of airway smooth muscle cells to a synthetic/proliferative phenotype by suppressing YAP expression [ 82 ]. Lipid A4 disrupts Smad/YAP signaling, resulting in reduced proliferation and migration of airway smooth muscle cells in asthma [ 83 ]. Additionally, pirfenidone has been demonstrated to suppress pulmonary fibrosis formation post‐SARS‐CoV‐2 infection by targeting the YAP/TAZ pathway [ 112 ]. The vitamin D receptor promotes adaptive remodeling of bile ducts by upregulating YAP in bile duct cells, thereby mitigating cholestatic liver injury [ 502 ]. VP, a small molecule compound, has shown effectiveness in disrupting the YAP–TEAD interaction and suppressing the Hippo pathway in different types of tumors and inflammatory disorders [ 154 , 300 , 503 , 504 ]. It effectively suppresses YAP activity, prevents abnormal differentiation of nasal epithelial cells, and reduces the release of inflammatory factors [ 28 , 42 , 46 ]. ARID1A directly interacts with and suppresses the transcriptional coactivators YAP and TAZ, which drive cell proliferation. By competing with YAP/TAZ for binding to TEAD, ARID1A hinders adult cardiomyocyte regeneration [ 148 ]. MYC enhances AMPK and suppresses YAP/TAZ activity in breast tumors [ 331 ]. VGLL4 inhibits YAP activity by competitively binding to TEADs, thereby halting the progression of gastric cancer [ 349 ]. TIAM1 inhibits colorectal cancer progression by impeding the interaction of YAP/TAZ with TEADs [ 454 ]. Phosphorylation of MST1/2 can hinder the activation of YAP [ 1 , 375 ]. In inflammatory conditions, phosphorylation of MST1/2 notably hinders YAP phosphorylation, leading to YAP activation and impeding its nuclear translocation, which in turn modulates the expression of inflammatory target genes [ 505 , 506 ]. Similarly, phosphorylated MST1/2 suppresses YAP activation in tumor cells, leading to extracellular retention and degradation of YAP [ 321 , 374 , 507 ]. Targeting MST1/2 phosphorylation proves to be an effective strategy for YAP inhibition [ 508 , 509 ]. NF2 exacerbates cardiac ischemia–reperfusion injury by activating MST1 and inhibiting YAP [ 150 ]. Adapalene can suppress YAP activation by triggering MST1/2, consequently relieving Staphylococcus aureus‐induced arthritis [ 510 ]. Phosphorylation of LATS1/2 is pivotal for Hippo pathway activation. Mechanistically, LATS1/2 phosphorylation directly boosts YAP phosphorylation, leading to YAP degradation and the inhibition of YAP1 transcriptional regulation [ 1 , 5 ]. In inflammatory diseases and tumors, LATS1/2 phosphorylation inhibits YAP activation, thereby modulating inflammation and tumor progression [ 320 , 511 , 512 ]. Glutamine is a key factor in maintaining cAMP/PKA activity and promoting LATS1/2 phosphorylation in tumor cells, ultimately repressing YAP activity [ 513 ]. Thus, promoting LATS1/2 phosphorylation emerges as a potential approach for YAP regulation.

As a pivotal gene in growth and development, YAP plays a crucial role in promoting cell proliferation and differentiation, impacting the body's immune status. YAP activation, whether through the Hippo‐dependent or independent pathway, triggers inflammation and the release of inflammatory factors in respiratory, cardiovascular, and digestive inflammatory diseases. Additionally, it drives tumor cell proliferation and differentiation in various cancer types, while modulating the tumor immune microenvironment to enhance tumor metastasis and progression. Despite these insights, the potential for YAP intervention remains underutilized, necessitating extensive future research. Currently, investigations into YAP in inflammatory and oncological diseases are notably limited, with little focus on YAP‐specific treatments and a lack of reported effective clinical trials. Many studies are confined to cellular or animal models. Given the potential toxicities and challenges in controlling various inhibitors, further safety assessments and clinical trials are crucial to advance YAP or Hippo pathway treatments. The overall inadequacy of translational research in inflammation and cancer highlights the pressing need for increased clinical drug studies to explore and validate potential therapies.

The Hippo pathway is a critical regulatory network that governs cell proliferation, differentiation, tissue development, and immune homeostasis. At its core, the Yes‐associated protein (YAP) plays a central role in this pathway [ 1 , 2 , 3 , 4 ]. In an active state of the Hippo pathway, LATS1/2 and their scaffold MOB1A/B are phosphorylated by MST1/2 and their scaffold protein SAV1. This phosphorylation event subsequently leads to the phosphorylation of YAP, inhibiting its activation and translocation, resulting in its sequestration in the cytoplasm and eventual degradation via the proteasome pathway. Conversely, when the Hippo pathway is inactive, the phosphorylation of MST1/2 and LATS1/2 is suppressed, leading to reduced phosphorylation of YAP. Consequently, YAP translocates to the nucleus, where it interacts with TEAD 1–4 transcription factors, initiating downstream gene transcription [ 5 , 6 , 7 , 8 , 9 ] (Figure  1 ). As a pivotal gene in the Hippo pathway, YAP plays a critical role in the initiation and progression of various inflammatory conditions in the body [ 10 , 11 , 12 ]. YAP serves as a crucial regulator in macrophage inflammation and the sensing of stiffness [ 13 ]. The activation of the ataxia telangiectasia mutated (ATM)–YAP1–pro‐IL‐18 pathway in epithelial cells, induced by telomere dysfunction, serves as a significant trigger for tissue inflammation [ 14 ]. Moreover, the YAP–TEAD transcriptional activity enhances autophagy flux and lysosomal acidification, thereby strengthening defenses against intracellular Staphylococcus aureus through an innate immune response [ 15 ]. YAP also maintains the stability of NOD‐like receptor protein 3 (NLRP3) by preventing its binding to the E3 ligase β‐TrCP1, thereby promoting inflammation [ 16 ]. Furthermore, YAP plays a role in the body's immune response to viral infections. The upregulation of ATP6V0d2 due to impaired serine metabolism leads to YAP lysosomal degradation, alleviating YAP‐mediated inhibition of the TBK1–interferon regulatory factor 3 (IRF3) axis and enhancing interferon‐β (IFN‐β)‐mediated antiviral innate immunity [ 11 ]. Additionally, lysophosphatidic acid induces Epstein–Barr virus lytic infection in epithelial cells through a YAP/TAZ‐dependent mechanism [ 17 ]. YAP has garnered significant attention as a key player in tumor development and metastasis. It has been implicated in the progression and inflammatory responses of malignant tumors such as liver cancer [ 18 ], lung cancer [ 19 ], and breast cancer [ 20 ]. Schematic diagram of the mechanism of hippo pathway. When the Hippo pathway is activated, it triggers the phosphorylation of MST1/2 and its scaffold protein SAV1. This phosphorylation, in turn, promotes the phosphorylation of LATS1/2 and its scaffold protein MOB1A/B. These phosphorylation events ultimately lead to the phosphorylation of YAP. Consequently, YAP either undergoes degradation or binds to 14‐3‐3 proteins, causing its retention in the cytoplasm. On the other hand, when the Hippo pathway is deactivated, YAP translocates to the nucleus and interacts with TEAD1–4. This interaction facilitates downstream gene transcription, thereby enabling YAP to exert its biological activities. YAP, Yes‐associated protein; TAZ, transcriptional coactivator with PDZ‐binding motif; SAV, protein salvador homolog 1; MST1/2, mammalian sterile 20‐like protein kinase 1/2; MOB1 A/B, MOB kinase activator 1A; LATS1/2, large tumor suppressor homolog 1/2; TEADs, TEA domain transcription factors. The figure is created by Figdraw. The activated state of YAP exerts a pivotal role in propelling the proliferation and metastasis of cancer cells. Moreover, it regulates the tumor immune microenvironment and inflammatory milieu by triggering inflammatory pathways. Nevertheless, the expression patterns and molecular pathways underlying YAP activation, whether they are Hippo pathway dependent or independent, vary significantly among different cell types in diverse diseases, and there is currently a dearth of comprehensive overviews. In light of the intricate role of YAP in disease pathogenesis, this study comprehensively summarizes the impacts of Hippo‐pathologically dependent and independent activation of YAP on various cell types in the context of inflammation and cancer, and delves into its correlations with these diseases. This encompasses an exploration of whether YAP activation is Hippo pathway dependent or independent in inflammatory diseases, such as chronic rhinosinusitis (CRS), asthma, cystic fibrosis (CF) and pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), viral infection in airway, cardiovascular inflammatory diseases, liver inflammatory diseases, colitis, nerve damage and cerebral hemorrhage, kidney injury, osteoarthritis, and diabetes. It also investigates YAP's role in different cancers, including head and neck cancer, nasopharyngeal carcinoma, thyroid cancer, malignant peripheral nerve sheath tumors, melanoma, breast cancer, gastric cancer, liver cancer, cholangiocarcinoma, pancreatic cancer, colorectal cancer, lung cancer, renal cancer, bladder cancer, and prostate cancer (Table  1 ). Additionally, the study summarizes the treatment strategies targeting different aspects of YAP in these diseases. Expression of YAP in respiratory diseases.

The authors declare no conflicts of interest.

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