Linderalactone attenuates pulmonary fibrosis by suppressing HIF-1α-associated ferroptotic stress

  • J Ethnopharmacol. 2026 Jun 12:364:121537. doi: 10.1016/j.jep.2026.121537.
Mengjie Qiu  1 ,  Xiao Zhou  1 ,  Aofeng Sun  2 ,  Huiwen Chen  3 ,  Xuan Xu  2 ,  Liuhui Zheng  2 ,  Yihan Ye  2 ,  Yini Xu  2 ,  Xiaofan Hong  2 ,  Dandan Zheng  2 ,  Chengguang Zhao  4 ,  Haiyang Zhao  5 ,  Lehe Yang  6
Affiliations
  • 1. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Institute of Life Sciences, Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, Zhejiang, 325035, China.
  • 2. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
  • 5. Institute of Life Sciences, Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
  • 6. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. Electronic address: [email protected].
PMID: 41839300 DOI: 10.1016/j.jep.2026.121537
Abstract

Ethnopharmacological relevance: Linderalactone is a sesquiterpene lactone isolated from Linderae Radix, a traditional Chinese medicinal herb used for pain and inflammatory disorders. Given the roles of hypoxia-related signaling, oxidative stress, and iron-dependent lipid peroxidation in fibrotic lung remodeling, linderalactone was evaluated as a natural product-derived anti-fibrotic lead.

Aim of the study: To evaluate the anti-pulmonary fibrosis activity of linderalactone and determine whether modulation of HIF-1α-dependent ferroptotic stress contributes to its underlying mechanism.

Materials and methods: BLM-induced pulmonary fibrosis mice and TGF-β1-stimulated lung fibroblasts were used. Histopathology, fibrosis markers, oxidative stress, ferroptotic stress-related markers, intracellular iron, and lipid peroxidation were assessed. HIF-1α was analyzed by immunostaining and manipulated by siRNA knockdown or DMOG-mediated stabilization. BODIPY-C11 and ferrostatin-1 were used to monitor lipid peroxidation and probe function.

Results: Linderalactone alleviated lung injury and Collagen deposition and suppressed fibroblast-to-myofibroblast transition. HIF-1α, colocalized with α-SMA-positive myofibroblasts, was downregulated. Linderalactone reduced malondialdehyde, PTGS2, lipid peroxidation, and intracellular iron, and restored glutathione, SLC7A11/xCT, and GPX4. HIF-1α knockdown phenocopied, whereas DMOG weakened, its protective effects. Fer-1 partially suppressed fibroblast activation, supporting a functional role for ferroptotic stress.

Conclusions: Linderalactone alleviates experimental pulmonary fibrosis by suppressing HIF-1α signaling and attenuating HIF-1α-associated oxidative stress and ferroptotic stress. These findings support the HIF-1α-ferroptotic stress axis as a plausible mechanism, provide proof-of-concept for linderalactone as a natural product-derived anti-fibrotic candidate, and warrant further pharmacokinetic and translational investigation.

Keywords
Ferroptotic stress; HIF-1α; Linderalactone; Oxidative stress; Pulmonary fibrosis.
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