Liver fibrosis is a pivotal pathological process in the progression of various chronic liver diseases toward cirrhosis, primarily driven by the activation of hepatic stellate cells. Recent studies have implicated dysregulation of circadian clock genes in the pathogenesis of hepatic disorders. The present investigation focused on the role of the circadian regulator nuclear receptor subfamily 1 group D member 1 (Rev‑erbα) in liver fibrosis and its mechanistic interplay with the NLR family domain containing protein 3 (NLRP3) inflammasome. A mouse model of liver fibrosis was established via carbon tetrachloride (CCl4) administration. The expression of Rev‑erbα was modulated pharmacologically using the agonist GSK4112 and the antagonist SR8278 to assess its impact on fibrogenesis. In parallel, lentiviral vectors were employed in in vitro studies to generate LX‑2 cell lines with Rev‑erbα overexpression or knockout. Transforming growth factor‑β1 (TGF‑β1) was applied to induce cellular activation, and subsequent effects on the NLRP3 inflammasome and its downstream mediators were analyzed. The extent of fibrosis and molecular alterations were evaluated using Masson's trichrome staining, Sirius Red staining, immunohistochemistry, western blotting and reverse transcription‑quantitative PCR. Rev‑erbα expression was significantly downregulated in both CCl4‑induced murine models and TGF‑β1‑activated LX‑2 cells. Pharmacological activation of Rev‑erbα attenuated hepatic fibrosis, evidenced by reduced collagen accumulation and suppression of fibrogenic markers (α‑smooth muscle actin, collagen 1 and TGF‑β1). By contrast, inhibition of Rev‑erbα exacerbated fibrotic responses. Mechanistically, Rev‑erbα activation inhibited NLRP3 inflammasome signaling and downstream pro‑inflammatory cytokines [interleukin (IL)‑18 and IL‑1β], underscoring its anti‑fibrotic function via NLRP3 pathway modulation. Rev‑erbα functions as a key negative regulator of hepatic fibrosis by suppressing NLRP3 inflammasome activation, representing a promising therapeutic target for the management of liver fibrosis.

Related Articles