Yes-associated protein 1 (YAP1)

Overview

Yes-associated protein 1 (YAP1) is a transcriptional coactivator protein that serves as a principal effector of the Hippo signaling pathway. Lacking its own DNA-binding domain, YAP1 acts by partnering with sequence-specific transcription factors—most notably the TEAD family—to switch on gene expression programs governing cell proliferation, survival, tissue growth, and regeneration. Its activity is controlled by upstream Hippo kinases, which phosphorylate YAP1 to retain it in the cytoplasm; when this restraint weakens, YAP1 translocates to the nucleus, where it can also form biomolecular condensates that concentrate transcriptional machinery and interacting partners such as JUNB and TCF12. Because it integrates mechanical cues from the extracellular matrix and cytoskeleton with biochemical signals, YAP1 is a central node in mechanotransduction.

In biomedical research, YAP1 is studied chiefly as an oncogenic and pro-fibrotic signaling protein alongside its paralog WWTR1 (TAZ). Elevated or sustained YAP1 activity is linked to tumor progression, stemness, and therapy resistance across Cancers including hepatocellular carcinoma, ovarian cancer, and small cell neuroendocrine carcinoma, and it intersects with pathways such as PI3K/AKT/mTOR and MAPK signaling and with the tumor microenvironment. YAP1 also drives maladaptive tissue responses—for example, tubular cell cellular senescence and epithelial–mesenchymal transition in kidney fibrosis, and TGF-β–associated remodeling—while conversely supporting beneficial repair in wound healing and neuronal differentiation through mechanotransduction. Additional work connects YAP1 to ferroptosis regulation via axes involving GPX4 and GLS1. These roles make YAP1 an actively pursued therapeutic target, addressed through approaches ranging from small-molecule inhibitors such as verteporfin to lipid nanoparticle–delivered siRNA that silences its expression.

Recent Publications Focus

Recent studies have continued to position YAP1 as a central mechanotransduction and transcriptional coactivator across diverse disease settings. In hepatocellular carcinoma associated with metabolic disorders, immunohistochemical analysis of resected tumors assessed YAP1 alongside CADM1 and SOX9, and found that Hippo-inactive status was common and associated with larger tumors; steatohepatitis and metabolic dysfunction-associated steatohepatitis were especially prominent in the metabolic disease group, supporting Hippo pathway proteins as potential therapeutic targets in MASH-related HCC 42482663Jul. In acute kidney injury, sustained YAP1 overexpression was linked to tubular cell cellular senescence, epithelial-mesenchymal transition, and renal interstitial fibrosis, while YAP1 knockdown reduced cellular senescence-associated and extracellular matrix-related signaling in HK-2 cells; senolytics and verteporfin both suppressed YAP1 activity and attenuated fibrosis in mouse AKI-to-CKD models 42381472Jul. YAP signaling was also implicated in osteosarcoma, where cisplatin-induced oxidative stress promoted nuclear YAP accumulation through repression of LATS1, and YAP inhibition reduced the accumulation of repressive chromatin marks and increased cisplatin sensitivity 41980058Apr.

Several publications focused on YAP1 as a therapeutic target in cancer and fibrosis using pharmacologic inhibition, nucleic acid delivery, or mechanobiology-based interventions. In ovarian cancer, RUNX2 was shown to transcriptionally regulate YAP1 and activate the YAP1/GLS1 axis, with ZDHHC14-driven S-palmitoylation of RUNX2 enhancing ferroptosis resistance and cisplatin resistance in vitro and in vivo 42149203May. In cervical cancer, YAP1 amplification defined a molecular subtype associated with poorer survival, and PI3Kα inhibition with alpelisib or inavolisib reduced YAP1 expression in PIK3CA-mutant models 41980433Apr. In uveal melanoma, restoration of upstream Hippo signaling by intravitreal delivery of LATS1 mRNA in lipid nanoparticle suppressed YAP activity and inhibited orthotopic tumor growth 41786044Mar. In liver fibrosis, a hepatic stellate cell-targeted verteporfin nanosystem was designed to inhibit YAP-mediated mechanical signaling and reduce extracellular matrix deposition and fibrotic activation 42066797May. A separate review of smart hydrogels highlighted YAP/TAZ-driven mechanotransduction as a key axis in multidrug resistance and tumor microenvironment remodeling 41963941Apr.

Other studies examined how YAP1 contributes to immune evasion, stress responses, and tumor biology. In esophageal squamous cell carcinoma, phosphoproteomic analysis indicated that YAP1 activation impaired anti-PD1 immunotherapy efficacy, whereas YAP1 inhibition or increased mitochondrial complex I expression improved CD8+ T cell-mediated killing and antitumor responses 41965870Apr. In colorectal cancer, a biomimetic nanoplatform carrying Defactinib inhibited the Integrin-FAK-YAP mechanotransduction axis, promoted YAP cytoplasmic sequestration, and enhanced cytotoxic T cell infiltration and checkpoint blockade activity 42002768Apr. In small cell neuroendocrine carcinoma, YAP1 protein expression was higher in extrapulmonary tumors than in pulmonary tumors, helping distinguish biologically distinct disease groups 42217423May. In sarcoma, eIF4A inhibition reduced translation of YAP1 and WWTR1, and combined YAP/TAZ knockdown induced apoptosis, linking YAP1 to translational control and poor clinical outcomes 41945393Apr. In addition, YAP1 was reported to participate in condensate formation under hyperosmotic stress, where JUNB and TCF12 were identified as essential condensate components required for downstream gene expression 42126959May.

Beyond oncology, YAP-related mechanobiology was also reported in regenerative and inflammatory models. A body temperature-responsive adhesive patch for diabetic wounds increased YAP signaling together with NRF2-related pathways, supporting extracellular matrix remodeling, immune modulation, and wound closure 42114775May. In airway remodeling, a traditional medicine formulation was reported to act through the S1PR2/ROCK1/YAP pathway in airway smooth muscle cells 41667044Feb. In neural differentiation, an anisotropic conductive collagen-based hydrogel activated integrin-FAK signaling and YAP nuclear accumulation during neuronal-like differentiation of PC-12 cells 42363939Jun. Finally, a study of polystyrene nanoplastics reported pyroptosis in HepG2 cells via the YAP1-cGAS-STING axis, further extending YAP1 involvement to environmental hepatotoxicity 41738323Feb.

What Changes, What Holds

1. Hippo-inactive YAP1 remains a useful marker of aggressive, metabolically linked HCC, but the new data do not revise its core role
REINFORCES The resected-tumor analysis strengthens the existing view that YAP1 tracks with tumor growth and disease progression, now extending that association to hepatocellular carcinoma arising in metabolic dysfunction-associated steatohepatitis. It supports Hippo-pathway proteins as candidate targets in this setting, but it does not displace the baseline account of YAP1 as a mechanotransduction-linked oncogenic coactivator 42482663Jul42381472Jul.

2. YAP1 inhibition is gaining traction as an anti-fibrotic strategy, while its stress-linked senescence role is being sharpened
REINFORCES The kidney studies fit the established picture that YAP1 drives maladaptive fibrosis, epithelial–mesenchymal transition, and senescence, and they add practical support for senolytics and verteporfin as ways to blunt that program in AKI-to-CKD transition. Nothing here conflicts with the baseline; instead, it makes the pro-fibrotic axis more actionable and ties it more directly to therapeutic suppression 42381472Jul41980058Apr.

3. YAP1 is now implicated in cisplatin resistance through oxidative-stress-dependent chromatin control in osteosarcoma
NEW DIRECTION This extends YAP1 beyond the baseline’s broad cancer and therapy-resistance framing into a specific stress-response mechanism not previously named there: cisplatin-induced oxidative stress promotes nuclear YAP accumulation after LATS1 repression, and YAP blockade alters repressive chromatin marks and drug sensitivity. The evidence is preclinical, so the mechanism needs validation in additional models, but it adds a new route by which YAP1 can shape chemotherapy response 41980058Apr.

4. YAP1 is increasingly a convergence point for ferroptosis, PI3K signaling, and Hippo restoration strategies in cancer and fibrosis
REINFORCES The ovarian, cervical, uveal melanoma, and liver-fibrosis studies collectively sharpen the baseline’s therapeutic-target theme rather than overturning it. They reinforce YAP1 as a downstream effector that can be suppressed by pathway inhibition, nucleic-acid delivery, or mechanobiology-based interventions, while also linking it to ferroptosis resistance and PI3K-driven expression. The main change is breadth and translational specificity, not a new biological role 42149203May41980433Apr.

5. YAP1-mediated mechanotransduction now appears to shape immune evasion and translational control as well as tumor growth
NEW DIRECTION The esophageal, colorectal, and sarcoma findings broaden the baseline by placing YAP1 in anti-PD1 resistance, checkpoint-blockade sensitization, and eIF4A-linked translational regulation. That is not a contradiction of its oncogenic role, but it adds immune and post-transcriptional layers that the Overview did not cover. The condensate result also strengthens the idea that YAP1 can organize nuclear stress responses through specific partners 41965870Apr42002768Apr.

6. YAP1 is being used to explain repair, differentiation, and environmental injury outside cancer, expanding its non-oncologic relevance
NEW DIRECTION These studies move beyond the Overview’s wound-healing and neuronal-differentiation examples by showing YAP-linked mechanobiology in diabetic wound closure, airway remodeling, and PC-12 neuronal-like differentiation, while also tying YAP1 to nanoplastic-induced hepatotoxic pyroptosis. None of this overturns the baseline; it shows that YAP1’s influence is broader and more context dependent than a cancer-centered reading would suggest 42114775May42363939Jun41738323Feb.