TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis. [Display omitted] •TM7SF3 knockdown increases HSC activation and worsens MASH fibrosis in vivo•Inhibiting TEAD1 splicing with an ASO reduces HSC activation and liver fibrosis•Active TEAD1ΔEx5 mediates HSC activation and liver fibrosis in MASH•TM7SF3 inhibits hnRNPU-mediated splicing of TEAD1 into the more active form Isaac et al. discover that deletion of the nuclear protein TM7SF3 accelerates hepatic stellate cell activation, promoting fibrosis in liver organoids, human cells, and MASH mice by inducing alternative splicing of TEAD1. Targeting TEAD1 splicing with a specific ASO deactivates HSCs and reduces MASH fibrosis, pointing to a potential therapeutic avenue.