Kv1.3 regulates macrophage immune function through PI3K/AKT signaling pathway to alleviate metabolic dysfunction-associated steatohepatitis.

Abstract

BACKGROUND AND AIM: The progression of metabolic dysfunction-associated steatohepatitis (MASH) is closely linked to macrophage-mediated inflammatory responses. The role of Kv1.3, a key voltage-gated potassium channel regulating macrophage function, in MASH remains unclear. This study investigated Kv1.3 blockade's therapeutic potential in MASH and its mechanism, focusing on the PI3K/AKT signaling pathway. METHODS: A Western diet (WD)-induced mouse model of MASH was established, and hepatic Kv1.3 was knocked down via AAV8-Kv1.3-shRNA. Hepatic steatosis, inflammation, and macrophage infiltration were evaluated. In vitro, LPS-stimulated RAW264.7 macrophages were treated with the Kv1.3 inhibitor ShK-186 to assess inflammatory cytokine (IL-6, TNF-α) production and migration. The GEO dataset (GSE222922) validated the PI3K/AKT signaling pathway involvement. RESULTS: Kv1.3 expression was significantly increased in WD-induced MASH mouse livers. Hepatic Kv1.3 knockdown alleviated liver injury, steatosis, and inflammation. In vitro, ShK-186 inhibited LPS-induced macrophage migration and cytokine production, and significantly reduced the PI3K/AKT phosphorylation. These effects were reversed by the PI3K agonist 740Y-P, confirming that Kv1.3 regulates macrophage function via the PI3K/AKT signaling. CONCLUSION: Kv1.3 modulates macrophage inflammation and migration through the PI3K/AKT signaling pathway, promoting MASH progression. Kv1.3 knockdown ameliorates MASH pathology, highlighting it as a promising therapeutic target. KEY MESSAGES: Kv1.3 drives MASH via macrophage PI3K/AKT signaling, worsening liver inflammation Macrophage Kv1.3 knockdown alleviates MASH pathology in WD-fed mice Kv1.3 is a potential therapeutic target for MASH, modulating liver inflammation.