Autoimmune diseases disproportionately affect women and present major clinical challenges globally. Historically, clinicians and immunologists evaluated autoreactive lymphocytes to explain the loss of immunological tolerance. However, emerging research demonstrates that non-hematopoietic stromal compartments actively dictate localized inflammatory responses. In this context, investigating Hippo signaling in autoimmunity has revealed fundamental insights into how tissue microenvironments govern immune responses. Stromal cells, including dermal fibroblasts and synovial cells, do not merely suffer passive bystander injury. Instead, they actively orchestrate leukocyte recruitment, cytokine synthesis, and extracellular matrix deposition. At the core of this regulatory axis is vestigial-like family member 3 (VGLL3), a transcriptional cofactor tied to Hippo signaling. Consequently, exploring communication between epithelial-stromal networks and invading immune cells provides novel opportunities for clinical translation. Furthermore, this paradigm reshapes our comprehension of systemic lupus erythematosus, systemic sclerosis, and chronic inflammatory arthritis.

The Hippo Pathway Architecture and Cellular Mechanotransduction

The canonical Hippo pathway operates as an evolutionary kinase cascade controlling organ size, cell proliferation, and tissue regeneration. In human cells, mammalian STE20-like kinases (MST1/MST2) collaborate with large tumor suppressor kinases (LATS1/LATS2). When active, these core kinases phosphorylate downstream transcriptional coactivators, specifically Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Phosphorylation subsequently sequesters YAP and TAZ in the cytoplasm, directing them toward proteasomal degradation. Conversely, unphosphorylated YAP and TAZ translocate into the cell nucleus. Within the nucleus, they bind TEA domain (TEAD) transcription factors to drive gene expression. Beyond soluble ligands, extracellular matrix stiffness and cellular tension directly regulate this pathway via mechanotransduction. Therefore, physical remodeling within inflamed tissues modulates kinase cascades independently of biochemical cues. In fibrotic skin or inflamed synovium, persistent mechanical tension suppresses core kinase activity. Consequently, active transcriptional effectors promote pathogenic cell activation. Thus, the Hippo cascade functions as a critical mechanical and biochemical bridge in dynamic tissue environments.

Connecting Hippo Signaling in Autoimmunity to Stromal Activation

Stromal compartments provide structural support for organs, yet pathological remodeling transforms them into potent disease drivers. Emerging evidence reveals that dysregulated Hippo signaling in autoimmunity reprograms quiescent fibroblasts into aggressive, inflammatory effector cells. For instance, in rheumatoid arthritis and systemic sclerosis, fibroblasts undergo phenotypic transitions that accelerate tissue destruction. Reduced LATS activity or sustained nuclear YAP/TAZ accumulation induces matrix metalloproteinases, pro-fibrotic factors, and cellular adhesion molecules. Consequently, activated stromal fibroblasts recruit circulating monocytes, dendritic cells, and autoreactive lymphocytes directly into inflamed tissue microenvironments. In addition, persistent Hippo pathway alterations protect pathogenic fibroblasts against normal apoptosis. These long-lived stromal cells continuously produce inflammatory chemokines such as CXCL12 and CCL2, establishing an amplified feedback loop. Therefore, local stroma creates an inflammatory sanctuary that resists conventional systemic immunosuppression. Understanding these alterations explains why peripheral remission does not always prevent progressive organ damage. By targeting stromal mechanotransduction, clinicians may ultimately interrupt localized joint erosion and stubborn cutaneous fibrosis.

Vestigial-Like Family Member 3 and Sex-Biased Autoimmunity

Clinical observations have long highlighted a remarkable female predominance across various autoimmune diseases, particularly systemic lupus erythematosus and Sjögren syndrome. Researchers historically attributed this disparity to circulating sex hormones or X-chromosome gene dosages. However, recent genomic profiling identifies vestigial-like family member 3 (VGLL3) as a pivotal female-biased transcriptional regulator. Female skin and epithelial tissues naturally express substantially higher baseline levels of VGLL3 than male tissues. Mechanistically, VGLL3 acts as a cofactor for TEAD transcription factors, competing against YAP and TAZ. When VGLL3 binds TEAD proteins, it drives a proinflammatory transcriptional program rather than classic developmental growth. For example, VGLL3 engagement induces robust expression of type I interferons, interferon-kappa, and the B-cell chemokine CXCL13. In animal models, transgenic overexpression of VGLL3 in the epidermis spontaneously triggers systemic autoimmunity, autoantibodies, and lupus nephritis. Furthermore, cellular stress amplifies VGLL3 upregulation in vulnerable tissues. Thus, VGLL3 represents a primary genetic driver explaining female predilection in chronic autoimmune conditions.

Interferon Signatures and Stromal-Immune Crosstalk

The type I interferon signature represents an established hallmark of pathology in systemic lupus erythematosus and dermatomyositis. Classically, researchers considered plasmacytoid dendritic cells the primary producers of circulating interferons in these diseases. Nonetheless, contemporary data show that keratinocytes and stromal fibroblasts generate substantial quantities of interferon-kappa under direct VGLL3 control. This locally produced interferon stimulates surrounding endothelial cells and resident macrophages via paracrine and autocrine pathways. As a direct result, adjacent cellular compartments upregulate interferon-stimulated genes, including ISG15 and MX1. In addition, this heightened interferon signature promotes B-cell activating factor (BAFF) secretion, supporting autoreactive B cells. Simultaneously, altered Hippo signaling lowers the cellular activation threshold against nucleic acids and ambient stress. Consequently, minor environmental insults, such as ultraviolet exposure, spark exaggerated interferon cascades in vulnerable patients. This self-amplifying network establishes a perpetual inflammatory state within peripheral organs. Therefore, the stromal-immune interface serves as an autonomous driving force for chronic inflammation, independent of systemic immune triggers.

Fibrotic Remodeling and Novel Therapeutic Horizons

Beyond perpetuating inflammation, dysregulated Hippo and VGLL3 signaling directly accelerates pathological tissue fibrosis in systemic sclerosis. Mechanical tension within rigid extracellular matrices suppresses upstream Hippo kinases, allowing unchecked TEAD-mediated gene expression. As a consequence, resting fibroblasts convert into contractile myofibroblasts that synthesize excessive collagen bundles and extracellular proteins. Moreover, these transformed myofibroblasts resist apoptotic elimination, leading to irreversible fibrotic changes within the skin and lungs. Conventional immunosuppressive agents, such as cyclophosphamide, demonstrate limited success against established fibrotic architecture. Fortunately, dissecting the Hippo-VGLL3 axis uncovers novel, highly specific therapeutic targets. Small chemical inhibitors that disrupt VGLL3-TEAD interactions offer tremendous potential to extinguish inflammatory gene programs selectively. Similarly, blocking mechanosensitive downstream kinases could normalize tissue compliance and interrupt destructive fibrotic feedback loops. Combining these stromal-directed compounds with standard immunosuppressive drugs might finally achieve meaningful disease modification. Thus, translating Hippo signaling discoveries opens promising pathways toward targeted therapeutics in rheumatology.

How does Hippo signaling influence stromal cell behavior during chronic inflammation?

The Hippo pathway regulates cellular mechanosensing and survival in stromal compartments. When kinase signaling becomes dysregulated, transcriptional coactivators like YAP and TAZ enter the cell nucleus. Consequently, quiescent fibroblasts transform into aggressive inflammatory effector cells that secrete abundant cytokines, matrix metalloproteinases, and chemokines. These altered stromal cells recruit peripheral leukocytes and resist apoptosis, thereby sustaining a localized inflammatory microenvironment that drives chronic tissue destruction and persistent fibrotic tissue remodeling.

Why is VGLL3 considered a key driver of female bias in autoimmune diseases?

Vestigial-like family member 3 exhibits baseline female-biased expression in healthy human skin and stromal tissues independent of circulating sex hormones. When VGLL3 complexes with TEAD transcription factors, it preferentially activates a robust network of inflammatory genes. Specifically, it stimulates type I interferons, CXCL13, and diverse inflammatory cytokines. This heightened basal immune readiness lowers the activation threshold in women, significantly increasing their lifetime susceptibility to systemic lupus erythematosus and related autoimmune conditions.

Can targeting the Hippo-VGLL3 pathway provide new therapeutic options for fibrosis?

Targeting the Hippo-VGLL3 interface represents a promising antifibrotic strategy for diseases like systemic sclerosis. Current therapies primarily suppress circulating immune cells but fail to halt progressive matrix deposition. Small molecules that disrupt VGLL3-TEAD interactions or inhibit mechanosensitive transcriptional coactivators directly prevent myofibroblast differentiation and promote cell clearance. Consequently, combining these stromal-directed therapies with standard immunosuppressive drugs could arrest refractory organ fibrosis, providing a balanced, comprehensive treatment strategy for patients with severe systemic disease.

Disclaimer: This content is for informational and educational purposes only and should not be considered medical advice. Always consult a qualified healthcare professional regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Plazyo O et al. Hippo signaling and vestigial-like family member 3 at the stromal-immune interface in autoimmunity. Trends Mol Med. 2026 Oct 02. doi: undefined. PMID: 42827068.

Yamaguchi N. Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway. J Biol Chem. 2020;295(29):9846-9856.

Billings FT 4th et al. The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity. JCI Insight. 2019;4(8):e127291.