ORIGINAL RESEARCH article
Front. Physiol.
Sec. Cell Physiology
Long noncoding RNA X-inactive-specific transcript promotes hepatic fibrosis by suppressing ferroptosis in hepatic stellate cells via the miR-663a/GPX4 axis
Provisionally accepted
- 1Guangdong Medical University, Zhanjiang, China
- 2Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- 3Central People's Hospital of Zhanjiang, Zhanjiang, China
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Aim: Hepatic fibrosis (HF) is a critical pathological stage in the progression of chronic liver diseases, where hepatic stellate cell (HSC) activation is a key event. Ferroptosis regulates the fate of HSCs and represents a potential anti-fibrotic target. Long non-coding RNA XIST (lncRNA-XIST) is involved in fibrosis-related diseases. This study investigated how lncRNA-XIST promotes HF by regulating ferroptosis through the microRNA-663 (miR-663a)/GPX4 axis. Methods: LX-2 HSCs were activated using ethanol at varying concentrations for different durations to determine optimal conditions. HSCs were intervened with small interfering RNA against lncRNA-XIST, and Liproxstatin-1 was applied. RT-qPCR, Western blotting, CCK-8, colony formation, LDH release, and biochemical assays assessed gene/protein expression, cell viability, proliferation, ferroptosis markers (Fe²⁺, MDA, GSH), and cell death. Dual-luciferase assays validated interactions among lncRNA-XIST, miR-663a, and GPX4. In vivo, an HF mouse model was established and treated with sh-XIST or miR-663a antagonists. Liver fibrosis was evaluated by histology, immunohistochemistry, and serum liver injury markers (ALT, AST, HYP). Results: Ethanol promoted LX-2 activation and upregulated lncRNA-XIST in a time- and dose-dependent manner (optimal: 100 mM, 24 h). LncRNA-XIST knockdown reduced α-SMA, CoL1A1, GPX4 levels, and cell proliferation while increasing ferroptosis markers (indicative of enhanced ferroptosis) and miR-663a expression. Mechanistically, lncRNA-XIST was found to act as a competing endogenous RNA (ceRNA) to sponge miR-663a, thereby upregulating GPX4 and inhibiting ferroptosis. In vivo, lncRNA-XIST was shown to promote HF progression via the miR-663a/GPX4 axis. Conclusions: LncRNA-XIST promotes HF by acting as a ceRNA for miR-663a, regulating GPX4, and suppressing ferroptosis to activate HSCs.
Keywords: glutathione peroxidase 4, hepatic fibrosis, Hepatic Stellate Cells, Long noncoding RNA X-inactive-specific transcript, miR-663a
Received: 29 Oct 2025; Accepted: 31 Dec 2025.
Copyright: © 2025 Dai, Zhong, Yang, Tan, Dai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ming-Yi Li
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