LncRNA gm40262 promotes liver fibrosis and parasite growth through the gm40262-miR-193b-5p-TLR4/Col1α1 axis.

Alveolar echinococcosis (AE) is a severe and life-threatening parasitic disease caused by Echinococcus multilocularis. Liver fibrosis is a significant pathological feature of advanced AE, characterized by the excessive production and accumulation of extracellular matrix (ECM). However, the precise underlying mechanism remains largely unknown. In this study, we show that the long noncoding RNA gm40262, predominantly expressed in hepatic stellate cells (HSCs), is upregulated in AE. Interestingly, its knockdown leads to liver fibrosis resolution, accompanied by a substantial suppression of parasite growth. Gm40262 functions by targeting miR-193b-5p to activate HSCs and stimulate their proliferation in a TGF-β-dependent manner, thereby promoting ECM production by upregulating Col1α1. Moreover, gm40262 is also involved in inflammation through the gm40262-miR-193b-5p-TLR4 axis. Our findings suggest that gm40262 plays a pivotal role in parasite-induced liver fibrosis through multiple mechanisms, highlighting its potential as a therapeutic target for hepatic fibrosis.

Importance: Echinococcus multilocularis is a tiny parasite with significant medical implications. The chronic parasitism of E. multilocularis in the liver generally leads to liver fibrosis, but the underlying mechanisms are poorly understood. We herein show that gm40262, a long noncoding RNA predominantly expressed in hepatic stellate cells (HSCs), is involved in hepatic fibrogenesis during infection by activating HSCs and promoting extracellular matrix production. The gm40262-orchestrating fibrogenesis occurs through the gm40262-miR-193b-5p-TLR4 and gm40262-miR-193b-5p-Col1α1 axes. The knockdown of gm40262 remarkably alleviates liver fibrosis, with decreased parasite growth. Our findings reveal a key role of gm40262 in liver fibrosis during E. multilocularis infection, rendering it a therapeutic target for hepatic fibrosis.