As an antioxidant, α‐lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α‐lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non‐small‐cell lung cancer (NSCLC) cell lines A549 and PC9. LA‐induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho‐PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme‐related antioxidative stress system. Administration of LA to the tumor‐bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

Background: Sustained pulmonary inflammation contributes significantly to lung carcinogenesis. Macrophages play a pivotal role in perpetuating inflammatory responses, undergoing a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis upon activation. The interplay between metabolic reprogramming and macrophage polarization remains poorly defined. The objective of this study is to examines the anti‐inflammatory mechanism of lipoic acid (LA), focusing on its ability to modulate immunometabolism in activated macrophages. Methods: We utilized lipopolysaccharide (LPS)‐stimulated RAW264.7 macrophages and a murine acute lung injury (ALI) model to evaluate the anti‐inflammatory effects of LA. Inflammatory cytokine expression was assessed by qPCR, ELISA, and Western blot. Metabolic profiling was performed using Seahorse XF technology to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), evaluating glycolytic and oxidative metabolic functions. Results: This study systematically elucidates the molecular mechanism by which LA modulates macrophage inflammatory responses through targeting the HIF1α/glycolysis axis. The main findings are as follows: (1) In LPS‐induced RAW264.7 macrophages, LA treatment significantly inhibited the expression of M1 macrophage markers (iNOS, CD86) and the secretion of proinflammatory cytokines (IL‐1β, IL‐6, etc.). (2) LA effectively reduced the expression of GSDMD, the key executor of pyroptosis, demonstrating its inhibitory effect on macrophage pyroptosis. (3) Metabolic analysis revealed that LA reversed LPS‐induced metabolic reprogramming by decreasing the ECAR and increasing the OCR, thereby suppressing glycolysis. (4) Mechanistic studies showed that siRNA‐mediated knockdown of HIF1α replicated both the anti‐inflammatory and metabolic regulatory effects of LA, confirming HIF1α as the key target in this pathway. (5) In an ALI mouse model, LA treatment significantly reduced HIF1α expression in lung tissues and effectively alleviated inflammatory responses, further validating the proposed mechanism. Conclusion: LA exerts potent anti‐inflammatory effects by targeting HIF1α‐mediated metabolic reprogramming in macrophages. Our results highlight the therapeutic potential of targeting immunometabolic pathways in inflammatory lung diseases, providing new insights into the mechanism by which LA ameliorates pulmonary inflammation.