2. Academic Validation
  3. Linderalactone attenuates pulmonary fibrosis by suppressing HIF-1α-associated ferroptotic stress

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

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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