ETHNOPHARMACOLOGICAL RELEVANCE: Swietenia macrophylla King is a traditional medicinal plant extensively utilized in Asia and its pharmacological properties primarily involve antidiabetic, anti-inflammatory, antioxidant, antibacterial, and antitumor effects. Swietenine (Swi), the major bioactive compound presents in the fruits of S. macrophylla, has demonstrated beneficial therapeutic effects on diabetic nephropathy (DN). However, the underlying mechanism through which Swi influences DN remains unclear. AIM OF THE STUDY: The current research aims to investigate the effects of Swi on DN and explore its underlying mechanisms associated with ferroptosis, both in vivo and in vitro. METHODS: A model of streptozotocin/high-fat diet (STZ/HFD)-induced Sprague-Dawley (SD) rats was employed to assess the effect of Swi on improving DN and resisting ferroptosis in vivo. Additionally, mouse podocyte cells (MPC-5 cells) were induced by high glucose (HG) and cultured to explore the potential mechanisms of Swi in treating DN in vitro. To further validate the protective effects of Swi, pathway-specific inhibitors were administered to HG-induced MPC-5 cells to confirm the involvement of the Akt/GSK-3β/Nrf2 signaling pathway in the inhibition of ferroptosis. A combination of proteomics, immunohistochemical staining, western blotting, and cell culture techniques was utilized to explore the pharmacological mechanisms of Swi. Furthermore, network pharmacology and molecular docking analyses were conducted to predict the targets of Swi in relation to DN, which were subsequently validated through Western blotting analysis. RESULTS: Administration of Swi significantly enhanced renal function and ameliorated pathological alterations in DN rats, as well as improved oxidative stress and inhibited ferroptosis. In vitro studies revealed that Swi dramatically improved the cell viability and mitigated oxidative stress, and inhibited ferroptosis via activating the Akt/GSK-3β/Nrf2 signaling pathway in HG-induced MPC-5 cells. CONCLUSION: This study demonstrates that Swi improves DN by inhibiting ferroptosis via activating Akt/GSK-3β/Nrf2 signaling pathway for the first time, thereby providing a scientific basis that Swi is expected to be a promising candidate drug for the treatment of DN.