Structural maintenance of chromosome protein 1A exacerbates liver fibrosis by enhancing hepatic stellate cell activation and extracellular matrix synthesis via laminin subunit gamma 2 activation.

Liver fibrosis is characterized by an abnormal buildup of extracellular matrix (ECM), which is primarily produced by hepatic stellate cells (HSCs). Laminin subunit gamma 2 (LAMC2) is an ECM protein whose functional role in hepatic fibrosis remains to be fully elucidated. Herein, we examine how LAMC2 contributes to liver fibrosis and explore the molecular mechanisms in both animal and cellular models. LAMC2 was knocked down in C57BL/6J mice with CCl4-induced liver fibrosis. Rescue experiments were conducted in sh-LAMC2-treated and recilisib (PI3K/Akt agonist)-treated mice. The transcription factors associated with LAMC2 in liver fibrosis were predicted and verified. Transforming growth factor (TGF)-β1-stimulated LX-2 cells (HSC line) were infected with lentiviral vectors for in vitro assays. LAMC2, which was enriched in the PI3K/Akt pathway, was increased in the liver tissues of mice treated with CCl4, and recilisib reversed LAMC2 knockdown-mediated alleviation of liver fibrosis in these mice. LAMC2 transcription in activated HSCs was caused by structural maintenance of chromosome protein 1A (SMC1A). The inhibitory effect of SMC1A knockdown on ECM accumulation and HSC activation was mitigated by LAMC2 overexpression. This study provides new insights and highlights the promising potential of the SMC1A/LAMC2/PI3K/Akt axis as a therapeutic target for liver fibrosis.