MASP1‑METTL3‑HAS2 axis aggravates liver fibrosis through HMW‑HA‑mediated senescence inhibition and LMW‑HA‑induced activation of hepatic stellate cells.

Abstract

The hepatic microenvironment undergoes dynamic remodelling in advanced liver fibrosis. Hyaluronic acid (HA), a key component of this fibrotic microenvironment, plays a key role in disease progression. While cellular senescence is one of the fates that activated HSCs undergo and is associated with fibrosis resolution, the relationship between HA and HSC senescence in advanced liver fibrosis remains unclear. This study aimed to elucidate the specific mechanisms by which HA regulates HSC senescence. Here, intrahepatic HSC transplantation confirmed that an advanced fibrotic microenvironment inhibited HSC senescence and led to its sustained activation. Mechanistically, low-molecular-weight (LMW) HA promotes HSC activation via the CD44-p38-ATF2 axis, while HMW-HA simultaneously inhibits HSC senescence through the TLR4-SerpinE1 axis. Furthermore, HA synthesis is mediated by MASP1. MASP1 enhances the m6A methylation of HAS2 via METTL3, leading to increased HAS2 mRNA levels and consequently elevated HMW-HA synthesis, and HYAL2 mediates the conversion of HMW‑HA to LMW‑HA. Targeted knockdown of MASP1 in the liver reversed HA metabolism, subsequently promoting HSC senescence and alleviating liver fibrosis. Therefore, targeting HA metabolism to induce HSC senescence for activated HSC removal may represent a novel therapeutic strategy for liver fibrosis.

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