Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Resveratrol dual efficacy in high-altitude hypoxia and NAFLD: inhibits ferroptosis by modulating key proteins, including HIF-1α, ACSL4, and TfR1.
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Zhao Minghui, Mu Hongfang, Ji Qian, Song Jiale, Zheng Fuyixuan, Liu Tianlong, Li Wenbin, Wang Rong
Аннотация
BACKGROUND: The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored.
OBJECTIVE: This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure.
METHODS: Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α.
CONCLUSION: Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
OBJECTIVE: This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure.
METHODS: Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α.
CONCLUSION: Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.