The Hippo pathway is an important signaling network that regulates tissue growth, cell proliferation, and tissue homeostasis. Its downstream YAP/TAZ–TEAD transcriptional module is closely associated with the initiation, progression, and treatment resistance of multiple tumors. As the druggability of the TEAD lipid-binding pocket and the YAP/TAZ–TEAD interaction interface has become increasingly clear, this transcriptional module is emerging as an important breakthrough point in Hippo pathway-targeted research.

Keywords: Hippo; YAP; TAZ; TEAD; NF2; TEAD palmitoylation; mechanotransduction; tumor targeting

1 Overview of the Hippo Signaling Pathway

1.1 Basic Functions of the Hippo Pathway

The Hippo pathway is a highly conserved growth-regulatory signaling pathway involved in controlling organ size, cell proliferation, apoptosis, stem cell states, tissue repair, and regeneration. It senses cell density, cell polarity, intercellular junctions, and mechanical signals generated by the extracellular matrix and converts this information into transcriptional regulation. When Hippo signaling is abnormally attenuated, cells may continuously activate growth- and survival-related transcriptional programs and contribute to the development and progression of multiple tumors.

1.2 Core Components of the Hippo Pathway

The canonical mammalian Hippo pathway is primarily composed of MST1/2, SAV1, LATS1/2, MOB1, and the downstream effectors YAP/TAZ. MST1/2 and SAV1 form the upstream kinase module and further promote the activation of LATS1/2 and MOB1; LATS1/2 directly regulate the phosphorylation and subcellular localization of YAP/TAZ. After entering the nucleus, YAP/TAZ bind to TEAD transcription factors. Therefore, the core signaling process can be summarized as:

MST1/2–SAV1 → LATS1/2–MOB1 → YAP/TAZ → TEAD

Figure 1. Schematic of the Hippo Signaling Pathway

2 The YAP/TAZ–TEAD Transcriptional Module

2.1 YAP and TAZ

YAP (Yes-associated protein) and TAZ [transcriptional coactivator with PDZ-binding motif, also known as WWTR1] are highly related transcriptional coactivators downstream of the Hippo pathway. Neither protein possesses a typical DNA-binding domain, and they function mainly by binding to other transcription factors. The phosphorylation status, protein stability, and cytoplasmic-to-nuclear translocation of YAP/TAZ collectively determine their transcriptional activity.

2.2 The TEAD Transcription Factor Family

The TEAD family comprises TEAD1, TEAD2, TEAD3, and TEAD4, all of which contain a TEA DNA-binding domain and a C-terminal domain that binds transcriptional coregulators. TEAD proteins can directly recognize DNA but possess limited intrinsic transcriptional activation capacity. They require binding to coactivators such as YAP and TAZ to efficiently drive target gene expression and therefore execute the terminal DNA-recognition and transcriptional functions of the Hippo pathway.

2.3 The YAP/TAZ–TEAD Complex

After entering the nucleus, YAP/TAZ form transcriptional complexes with TEAD1–4. TEAD recognizes DNA regulatory regions, whereas YAP/TAZ provide transcriptional coactivator functions. These complexes promote the expression of target genes such as CCN1/CYR61, CCN2/CTGF, ANKRD1, and AMOTL2 and regulate cell proliferation, survival, migration, extracellular matrix remodeling, and stemness maintenance. Therefore, YAP/TAZ–TEAD is not a single-protein target but an important terminal transcriptional module of the Hippo pathway.

3 Regulation of YAP/TAZ–TEAD by the Hippo Pathway

3.1 The MST–LATS Kinase Cascade

(1) Activation of MST1/2 and LATS1/2

Following Hippo pathway activation, MST1/2 promote the activation of LATS1/2 and MOB1 with the involvement of SAV1 and other regulatory proteins, forming an important kinase cascade that inhibits YAP/TAZ. In addition to MST1/2, certain members of the MAP4K family can participate in the regulation of LATS1/2, allowing YAP/TAZ to be controlled by multiple upstream signals.

(2) YAP/TAZ Phosphorylation

Activated LATS1/2 phosphorylate YAP and TAZ. For example, phosphorylation of YAP at Ser127 promotes its binding to 14-3-3 proteins, retaining YAP in the cytoplasm; other phosphorylation events can also promote protein degradation. TAZ is similarly regulated through LATS-dependent phosphorylation.

(3) Inhibition of YAP/TAZ-Mediated Transcription

When the Hippo pathway is active, YAP/TAZ cannot continuously accumulate in the nucleus, and their ability to form effective transcriptional complexes with TEAD decreases, thereby suppressing the expression of growth-related genes.

3.2 Hippo Inactivation and TEAD Transcriptional Activation

When NF2 is lost, LATS1/2 function declines, or other upstream mechanisms that maintain tumor-suppressive Hippo signaling are disrupted, YAP/TAZ phosphorylation decreases and the proteins accumulate in the nucleus. Nuclear YAP/TAZ bind to TEAD and enhance the transcription of genes such as CCN1, CCN2, and ANKRD1, shifting cells from a Hippo-mediated growth-inhibitory state to a YAP/TAZ–TEAD-driven transcriptionally active state.

3.3 Mechanical Forces, GPCRs, and Metabolic Signals

(1) Mechanotransduction

Extracellular matrix stiffness, cell spreading, F-actin polymerization, and myosin contractility can all influence YAP/TAZ. Higher cytoskeletal tension and Rho–ROCK activity generally promote the nuclear accumulation of YAP/TAZ, whereas disrupting F-actin or reducing cellular contractility can inhibit their activity.

(2) GPCR Signaling

Lipid mediators such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) can regulate YAP/TAZ through specific GPCRs and Rho-family small GTPases, enabling the Hippo pathway to respond to different types of extracellular stimuli.

(3) The Mevalonate Pathway

Isoprenoid intermediates produced by the mevalonate pathway participate in the protein prenylation of Rho and other small GTPases. Inhibiting this metabolic pathway can alter Rho localization and activity, thereby affecting cytoskeletal states and YAP/TAZ nuclear translocation and establishing a connection between cellular metabolic status and Hippo transcriptional output.

4 Why YAP/TAZ–TEAD Has Become a Breakthrough Point in the Hippo Pathway

4.1 Hippo Upstream Regulation Is Highly Dispersed

NF2, AMOT, KIBRA, the FAT family, cell-polarity proteins, mechanical forces, GPCRs, and metabolic networks can all regulate Hippo signaling. YAP/TAZ abnormalities in different tumors may be driven by different upstream factors, making it difficult for inhibition of a single upstream node to cover all YAP/TAZ-activated contexts.

4.2 Direct Drugging of YAP/TAZ Has Limitations

YAP and TAZ are not enzymes with well-defined catalytic centers. Their functions mainly depend on protein–protein interactions, and they contain multiple flexible structural regions while lacking the deep ATP-binding pockets exploited by conventional kinase inhibitors. Developing highly selective small-molecule inhibitors that directly target YAP/TAZ therefore presents substantial structural design challenges.

4.3 TEAD Provides a Defined Druggable Structure

The C-terminal domains of TEAD1–4 contain a conserved hydrophobic lipid-binding pocket capable of autopalmitoylation. This pocket can be occupied by small molecules that reduce YAP/TAZ–TEAD transcriptional activity by altering TEAD conformation, lipid modification, or coactivator binding, providing a defined small-molecule intervention site within the terminal Hippo transcriptional module.

4.4 Different Upstream Abnormalities Converge on a Common Transcriptional Output

NF2 loss, LATS1/2 dysfunction, increased mechanical tension, and certain oncogenic signals occur at different regulatory levels but ultimately manifest as YAP/TAZ nuclear accumulation and enhanced TEAD-dependent transcription. Direct inhibition of TEAD or disruption of the YAP/TAZ–TEAD complex can bypass the complex upstream regulatory network and restrict abnormal Hippo signaling at the level of its common transcriptional output.

5 Major Strategies for Targeting YAP/TAZ–TEAD

5.1 Inhibition of the TEAD Lipid-Binding Pocket

The central TEAD lipid-binding pocket is currently one of the most extensively studied drug-binding regions. Compounds such as K-975 and VT3989 can enter this pocket and regulate TEAD function through covalent or noncovalent mechanisms, thereby reducing YAP/TAZ-driven transcriptional output. Compared with directly targeting YAP/TAZ, this approach has a more clearly defined structural basis and has become an important direction in TEAD drug development.

5.2 Blocking YAP/TAZ–TEAD Protein Interactions

Several key interaction interfaces exist between YAP/TAZ and TEAD, and certain structural regions are important for complex stability. Small molecules designed against these interfaces can directly compete with YAP/TAZ for TEAD binding and thereby prevent transcriptional complex formation. IAG933 represents a development strategy that directly interferes with YAP/TAZ–TEAD protein interactions and provides a pharmacological route distinct from strategies targeting the central TEAD lipid-binding pocket.

5.3 Targeted Degradation of TEAD

Targeted protein degradation technologies such as PROTAC can recruit E3 ubiquitin ligases to induce TEAD ubiquitination and proteasomal degradation, reducing TEAD protein levels rather than merely occupying its functional pocket. With the development of selective TEAD degraders and pan-TEAD degradation strategies, targeted degradation is emerging as a new intervention approach beyond conventional TEAD inhibition.

5.4 Regulation of Upstream Hippo Signaling

MST1/2, LATS1/2, Rho–ROCK, F-actin, and the mevalonate pathway can all serve as entry points for regulating YAP/TAZ. These strategies primarily regulate the pathway by altering YAP/TAZ phosphorylation, stability, or subcellular localization and have important value in Hippo mechanistic research and combination therapy exploration.

6 Research Progress in YAP/TAZ–TEAD Targeting

6.1 K-975

(1) Mechanism of Action

K-975 binds to the central TEAD lipid-binding pocket and regulates TEAD function through covalent interactions, inhibiting the transcriptional output mediated by the YAP/TAZ–TEAD complex. Research on this compound has further demonstrated that the internal TEAD lipid pocket can serve as a direct pharmacological intervention site for the terminal Hippo transcriptional module.

(2) Preclinical Research

In Hippo-aberrant models such as NF2-deficient malignant mesothelioma, K-975 has demonstrated pronounced inhibition of cell growth and in vivo antitumor activity, providing important preclinical evidence for the development of TEAD inhibitors in YAP/TAZ-dependent tumors.

6.2 VT3989

(1) Clinical Proof of Concept

VT3989 is an orally administered TEAD palmitoylation inhibitor. Early clinical studies have observed antitumor activity in patients with advanced solid tumors, particularly mesothelioma, providing human proof of concept for direct pharmacological intervention in the Hippo–YAP/TAZ–TEAD axis.

(2) Therapeutic Window

Adverse events including proteinuria, peripheral edema, and fatigue have been observed in clinical studies. Because TEAD also participates in normal tissue homeostasis, renal safety, TEAD isoform selectivity, and the therapeutic window have become important directions for the subsequent optimization of this drug class.

6.3 IAG933

(1) Blocking YAP/TAZ–TEAD Interactions

IAG933 directly targets the YAP/TAZ-binding region on the TEAD surface and competitively prevents YAP/TAZ from forming effective transcriptional complexes with TEAD. Compared with K-975, VT3989, and other strategies that primarily target the central TEAD lipid-binding pocket, IAG933 provides another drug-development route that directly interferes with the YAP/TAZ–TEAD protein interaction interface.

(2) Clinical Development

IAG933 has entered early-stage clinical studies focusing on mesothelioma and solid tumors with NF2 or LATS1/LATS2 abnormalities or YAP/TAZ fusions. Its development further indicates that transcription-regulatory protein interaction interfaces previously considered difficult to drug may also be directly targeted pharmacologically.

6.4 KIRREL1

(1) Hippo Negative-Feedback Regulation

KIRREL1 is a transmembrane protein that can interact with SAV1 and LATS1/2 and promote MST1/2-mediated LATS activation, thereby enhancing the inhibition of YAP/TAZ. YAP/TAZ can in turn promote KIRREL1 expression through TEAD, forming a negative-feedback regulatory loop within the Hippo pathway.

(2) A Cell-Surface Research Entry Point

KIRREL1 expression correlates with that of certain canonical YAP/TAZ target genes. Because it is localized to the cell membrane, KIRREL1 may also serve as a cell-surface research marker reflecting YAP/TAZ activity, providing a new entry point for identifying and targeting YAP/TAZ-active tumors.

7 Products

7.1 Products for YAP/TAZ–TEAD and Core Hippo Pathway Research

7.2 Products for Cytoskeletal and Rho–ROCK Mechanotransduction Research

7.3 Products for Mevalonate and GPCR Signaling Research

YAP/TAZ–TEAD converges complex upstream Hippo signals into a relatively concentrated transcriptional output, while the druggability of the TEAD lipid-binding pocket and YAP/TAZ interaction interface addresses the long-standing lack of direct intervention sites in this pathway. With the development of TEAD inhibition, protein-interaction blockade, and targeted degradation strategies, YAP/TAZ–TEAD is becoming an important direction in Hippo pathway-targeted research.

References

[1] Harvey KF, Tang TT. Targeting the Hippo pathway in cancer. Nat Rev Drug Discov. 2025;24:852–869.

[2] Kaneda A, Seike T, Danjo T, et al. The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma. Am J Cancer Res. 2020;10(12):4399–4415.

[3] Chapeau EA, Sansregret L, Galli GG, et al. Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers. Nat Cancer. 2024;5:1102–1120.

[4] Gu Y, Wang Y, Sha Z, et al. Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers. Cell Rep. 2022;40(9):111296.

[5] Yap TA, Kwiatkowski DJ, Dagogo-Jack I, et al. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med. 2025;31:4281–4290.

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