Apelin aggravates inflammatory response and hepatic steatosis in alcohol-associated liver disease via ERK signaling pathway

Front Pharmacol. 2026 Sep 30;17:1912482. doi: 10.3389/fphar.2026.1912482. eCollection 2026.

ABSTRACT

BACKGROUND: Though apelin is involved in cardiovascular, metabolic, and homeostasis disorders, its role in alcohol-associated liver disease (ALD) remains unclear. This study aimed to investigate the mechanism of apelin in promoting hepatic inflammation in ALD.

METHODS: RAW 264.7 macrophages and a chronic alcohol-fed C57BL/6 mouse model were used. Apelin activated ERK1/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression. Inflammatory and proliferative markers (MCP-1, IL-6, PCNA) were assessed by qRT-PCR and western blot. ERK signaling was evaluated using the inhibitor PD98059. Liver pathology was examined by H&E and Oil Red O staining.

RESULTS: Alcohol upregulated apelin expression in RAW 264.7 cells. Apelin-13 increased MCP-1 and PCNA expression in time- and dose-dependent manners. Apelin overexpression enhanced, while siRNA knockdown reduced, inflammatory and proliferative gene expression. Apelin activated ERK1/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression. In vivo, apelin overexpression exacerbated steatosis, ballooning degeneration, and inflammatory infiltration, with elevated MCP-1, IL-6, and PCNA levels.

CONCLUSION: Apelin aggravates inflammatory responses and hepatic steatosis in ALD via the ERK signaling pathway, suggesting that the apelin/APJ/p-ERK/inflammation axis may represent a novel therapeutic target for ALD.

PMID:42876529 | PMC:PMC13661315 | DOI:10.3389/fphar.2026.1912482