Mandi, V. | Search bioRxiv

bioRxiv2026

Hepatocyte TEAD1 drives epithelial-stromal remodeling during cholestatic liver injury

Background & AimsPrimary sclerosing cholangitis (PSC) is a progressive cholangiopathy characterized by ductular remodeling, inflammation, and periportal fibrosis, for which effective medical therapies remain limited. The Hippo pathway effector TEAD1 has been implicated in liver regeneration and fibrogenesis; however, its role in cholestatic injury remains poorly defined. We investigated whether hepatocyte TEAD1 regulates injury-associated remodeling in a PSC-mimicking model and whether this mechanism is conserved in human PSC liver. MethodsHepatocyte-specific TEAD1 knockout mice (Alb-TEAD1-/-) and littermate controls were subjected to DDC-induced cholestatic injury. Ductular reaction, fibrosis, inflammation, and bile acid-related gene programs were assessed by histology, immunostaining, and gene expression analyses. Translational relevance was evaluated using bulk and single-cell transcriptomic datasets from human PSC liver. ResultsHepatocyte TEAD1 deletion attenuated DDC-induced fibrosis, ductular expansion, and inflammatory cell accumulation, while preserving hepatocyte proliferative responses. TEAD1-deficient livers exhibited reduced expression of profibrotic mediators, including Spp1, Ctgf, and Cyr61, with decreased extracellular matrix deposition. In contrast, canonical transcriptional adaptations to cholestatic stress, including suppression of bile acid uptake, induction of efflux pathways, and repression of bile acid synthesis genes, were preserved in the absence of TEAD1. Analysis of human PSC datasets demonstrated coordinated upregulation of TEAD1 and TEAD-associated target genes. Single-cell transcriptomic analysis further revealed hepatocyte-enriched TEAD1 expression and activation of a TEAD1 target gene program across all hepatic zones in PSC, with effect sizes exceeding those observed in non-parenchymal populations. TEAD1 activation was accompanied by co-expression of profibrotic mediators and downregulation of hepatocyte differentiation markers, consistent with a maladaptive hepatocyte state. ConclusionsHepatocyte TEAD1 drives ductular, inflammatory, and fibrogenic remodeling during cholestatic injury without disrupting bile acid metabolic adaptation. These findings identify TEAD1 as a hepatocyte-intrinsic regulator of epithelial-stromal crosstalk and establish conserved activation of this pathway in human PSC, supporting TEAD-directed signaling as a therapeutic target.

pathology↗

bioRxiv2025

TEAD1 is a novel regulator of NRF2 and oxidative stress response in cardiomyocytes

BACKGROUNDTEAD1, the mammalian Hippo pathway-regulated transcription factor, plays a critical and non-redundant role in maintaining cardiomyocyte (CM) homeostasis. However, the specific cellular pathways regulated by TEAD1 in CMs remain poorly defined. We hypothesized that TEAD1 has an essential, cell-autonomous role in the CM oxidative stress response by directly regulating the transcription of NRF2, the master regulator of oxidative stress response. METHODS AND RESULTSTamoxifen-induced conditional CM-specific TEAD1 deletion in adult mice leads to acute heart failure (HF) and altered expression of antioxidant genes. In silico analysis of publicly available RNA-seq data from human hearts with end-stage dilated (DCM) and ischemic (ICM) cardiomyopathy revealed significant downregulation of TEAD1 transcript levels and a positive correlation between TEAD1 and NRF2 gene expression. ChIP-seq and ATAC-seq in adult mouse hearts confirmed TEAD1 occupancy at promoter/enhancer elements within open chromatin regions of multiple antioxidant genes, including NRF2 and its targets. Ex vivo and in vitro TEAD1 knockout in primary neonatal and adult murine CMs, as well as in H9C2 cells, resulted in significantly increased cellular and mitochondrial ROS le, accompanied by a marked decrease in NRF2 expression and promoter-luciferase activity, under both basal and oxidative stress conditions. Mosaic, conditional deletion of TEAD1 in [~]40-50% of murine heart CMs provided a novel in vivo model for studying TEAD1-regulated pathways in the heart, independent of the confounding effects of HF. This model demonstrated reduced NRF2 expression and heightened oxidative stress in neonatal and adult TEAD1 mosaic knockout hearts. Notably, 8OHdG staining identified oxidative DNA damage in TEAD1-deficient CMs compared to TEAD1-expressing CMs within the mosaic knockout hearts. Upon in vivo AngII infusion, TEAD1 mosaic knockout hearts showed a significant increase in oxidative stress markers and an impaired NRF2 response. Overexpression of human TEAD1 restored NRF2 activity and mitigated ROS accumulation in TEAD1 knockout CMs in vitro. Furthermore, TEAD1 deletion in human iPSC-derived CMs resulted in increased oxidative stress and downregulation of NRF2 expression and functional activity, confirming the requirement of TEAD1 in NRF2-mediated oxidative stress response in human CMs. Collectively, these findings establish that TEAD1 is essential for NRF2 expression and activity under both basal and AngII-induced conditions and plays a crucial role in the oxidative stress response in CMs. CONCLUSIONSTEAD1 is a cell-autonomous, direct transcriptional regulator of NRF2 and the cardiomyocyte (CM) oxidative stress response. Its gene expression, which directly correlates with NRF2 transcript levels in the human myocardium, is significantly downregulated in human end-stage heart failure, potentially compromising the oxidative stress response in the failing heart.

molecular biology↗