BTN2A2 Alleviates Arsenic-Induced Liver Fibrosis by Suppressing Pyroptosis and Inflammation

Arsenic is a ubiquitous environmental pollutant that accumulates in the liver upon chronic exposure, driving hepatic injury and carcinogenesis. Hepatic fibrosis is a critical juncture in the progression from chronic damage to cirrhosis and cancer, yet therapeutic strategies targeting the fibrotic stage of arsenic-induced liver disease remain limited. Here, we investigated whether butyrophilin subfamily 2 member A2 (BTN2A2) serves as a protective regulator in arsenic‑induced liver fibrosis and explored its underlying mechanisms. Mice were randomly divided into four groups (n = 6 per group): untreated control, 40 ppm sodium arsenite (NaAsO₂), 80 ppm NaAsO₂, and an intervention group receiving continuous 80 ppm NaAsO₂ in drinking water for 36 weeks with BTN2A2 administration during weeks 32‑36. After 36 weeks, arsenic burdens in urine and hepatic tissue confirmed substantial accumulation, accompanied by a dose‑dependent decline in hepatic BTN2A2 protein expression. Remarkably, BTN2A2 administration alleviated liver fibrosis but did not reduce arsenic accumulation. At the molecular level, BTN2A2 suppressed the hepatic expression of pro‑inflammatory mediators, including interleukin-17 (IL-17), and pyroptotic effectors, concomitantly decreasing NLR family pyrin domain containing 3‌ (NLRP3), Caspase‑1, and Gasdermin D N-terminal domain (GSDMD‑N) protein levels. Flow cytometry further revealed that BTN2A2 restored the intrahepatic immune landscape by reducing T helper 17 cells and increasing regulatory T cells (Tregs). Mechanistically, BTN2A2 suppressed arsenite-triggered NLRP3/Caspase-1/GSDMD-N pyroptotic signaling in hepatocytes and reduced IL-17 secretion, thereby limiting hepatic stellate cell-mediated extracellular matrix deposition. Conversely, siRNA‑mediated knockdown of BTN2A2 in hepatocytes significantly unleashed the pyroptotic cascade, reinforcing BTN2A2 as a genuine negative regulator of hepatocyte pyroptosis. Collectively, these findings demonstrate that BTN2A2 attenuates arsenic‑induced hepatic fibrosis by suppressing IL‑17‑driven inflammation and pyroptosis, supporting its potential as a therapeutic target for environmental arsenic‑associated fibrotic liver disease.