Journal of ethnopharmacology · 2026
Linderalactone attenuates pulmonary fibrosis by suppressing HIF-1α-associated ferroptotic stress.
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Qiu Mengjie, Zhou Xiao, Sun Aofeng, Chen Huiwen, Xu Xuan, Zheng Liuhui, Ye Yihan, Xu Yini, Hong Xiaofan, Zheng Dandan, Zhao Chengguang, Zhao Haiyang, Yang Lehe
Аннотация
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.
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.