Protective Effects of Total Alkaloids of Rhizoma Corydalis Against Neuronal Ferroptosis Through a PPARγ-Dependent Mechanism in Diabetes-Associated Cognitive Impairment

Objectives: Previous studies from our laboratory have established a strong correlation between diabetes-associated cognitive impairment (DACI) and neuronal ferroptosis. This study aimed to elucidate the therapeutic mechanisms of total alkaloids of rhizoma corydalis (TAC) in mitigating DACI, with a specific focus on its modulation of neuronal ferroptosis via the PPARγ pathway. Methods: Therapeutic targets were predicted utilizing bioinformatics, molecular docking, and single-cell RNA sequencing (scRNA-seq) analyses. In vivo, a DACI rat model was established via a high-fat/high-sugar diet coupled with streptozotocin (STZ) intraperitoneal injection, followed by TAC administration. In vitro, HT22 cell injury was induced by palmitic acid and high glucose (PA + HG) exposure. Small interfering RNA (siRNA)-mediated PPARγ knockdown was employed to validate the protective mechanisms of TAC. Results: Multi-omics and computational analyses identified neuronal PPARγ as the central target mediating the anti-ferroptotic effects of TAC. In vivo assessments demonstrated that TAC administration significantly attenuated spatial memory deficits, dyslipidemia, and insulin resistance in diabetic rats. Furthermore, TAC mitigated hippocampal neuronal injury and mitochondrial morphological abnormalities, decreased iron overload and lipid peroxidation, and normalized the expression profiles of ferroptosis-associated proteins. In vitro assays, corroborated by siRNA-mediated knockdown, confirmed that TAC specifically upregulates PPARγ, which subsequently activates the Nrf2/HO-1 signaling axis and enhances GPX4 expression, ultimately conferring resistance against neuronal ferroptosis. Conclusions: TAC emerges as a highly promising therapeutic candidate for DACI, exerting its neuroprotective efficacy intrinsically through the targeted activation of PPARγ to abrogate neuronal ferroptosis.