{
  "abstract": "Background Liver fibrosis poses a major global health challenge due to its rapidly increasing incidence and lack of effective therapies. Chloride ions (Cl −) are critical regulators of cellular homeostasis, and alterations in intracellular chloride concentration ([Cl−]i) influence inflammation and immune responses. However, their role in liver fibrosis remains unexplored. This study aims to investigate the impact of elevated [Cl−]i on hepatic stellate cell (HSC) activation and its underlying mechanisms.Methods Human LX2 and rat HSC-T6 cells were cultured in media with varying Cl − concentrations. [Cl−]i was measured using MQAE fluorescent probe and ELISA. Fibrosis markers (α-SMA, Col1a1), endoplasmic reticulum stress (ERS) markers (GRP78, p-PERK, p-Eif2α, ATF4, CHOP), reactive oxygen species (ROS), and NLRP3 inflammasome signaling components (NLRP3, cleaved caspase-1, mature IL-1β, HMGB1) were assessed via qPCR, Western blot, and fluorescent assays. Mouse liver fibrosis models were established using CCl4 and CDAHFD. The chloride channel inhibitor DIDS was administered intraperitoneally. Fibrosis was evaluated by histology and molecular analyses.Results Activated HSCs exhibited elevated [Cl −]i. High-chloride (158.5 mM) medium promoted HSC activation and triggered ERS, as indicated by upregulation of GRP78, p-PERK, p-Eif2α, ATF4 and CHOP. Mechanistically, high chloride induced ROS accumulation and activated the NLRP3 inflammasome pathway, evidenced by increased NLRP3 expression, caspase-1 cleavage, and subsequent maturation and release of IL-1β and HMGB1. The ERS inhibitor 4-PBA, the PERK inhibitor, or the chloride channel inhibitor DIDS attenuated these effects. Furthermore, DIDS suppressed TGF-β1-induced HSC activation. In murine liver fibrosis models, DIDS administration significantly ameliorated liver fibrosis, concurrent with inhibition of the ERS and NLRP3 inflammasome pathways.Conclusions Increased [Cl −]i promotes HSC activation by inducing ERS and subsequent NLRP3 inflammasome activation, leading to a pro-inflammatory and pro-fibrotic response. Targeting chloride channels with DIDS inhibits this pathogenic cascade and alleviates liver fibrosis, revealing a novel chloride-dependent signaling axis in fibrogenesis and its potential as a therapeutic target.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Shun Yao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Jingguo Li"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Jiaxing Zhu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Jiaxing An"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Hai Jin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Xuemei Liu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Biguang Tuo"
    }
  ],
  "title": "IDDF2026-ABS-0144 Increased intracellular chloride concentration promotes hepatic stellate cell activation via endoplasmic reticulum stress and NLRP3 inflammasome signaling",
  "uid": "cc026d08-7dec-58a9-b64a-c99e83f4b101"
}