Liver sinusoidal endothelial TGF-β signaling accelerates partial endothelial–mesenchymal transition and MASH through Notch

BACKGROUND n = 3 mice/condition, depending on the parameter). Mechanistically, we found that differentiation of these biphenotypic cells was regulated by TGF-β signaling. Inhibition of TGF-β signaling in LSECs suppressed partial EndMT and attenuated MASH progression (p <0.01-0.0001; n = 10 mice/condition). In addition, we discovered that Notch signaling in LSECs, which is activated in response to MASH, was positively regulated by TGF-β signaling and had a crucial role in both the generation of biphenotypic cells and MASH progression (p <0.01-0.0001; n = 3-10 samples/condition). CONCLUSIONS: Our findings reveal that a pathogenic TGF-β/Notch axis drives MASH progression by inducing partial EndMet in LSECs, thereby establishing LSEC-targeted intervention as a promising therapeutic strategy for this disease. IMPACT AND IMPLICATIONS: This study reveals a novel biphenotypic LSEC population generated via TGF-β-driven partial EndMT, establishing LSEC dysfunction as an active driver of MASH progression. By elucidating the TGF-β/Notch crosstalk in LSEC partial EndMT, our findings provide new mechanistic insights into MASH pathogenesis. Thus, these results highlight TGF-β signaling in LSECs as a promising therapeutic target. Future work should focus on LSEC-specific delivery systems and validation in cohorts of patients with MASH.