Fingered Citron Extract Ameliorates Diabetes‐Related Depression via Targeting SRC ‐Mediated Insulin Signaling and Neuroinflammation

Diabetes‐related depression (DD) is a challenging comorbidity characterized by self‐reinforcing interactions between metabolic dysfunction and affective disturbance, while conventional antidepressants and glucose‐lowering drugs often yield suboptimal outcomes with adverse effects. This study investigated the therapeutic potential of fingered citron extract (FCE), traditionally used for metabolic and inflammatory conditions, in alleviating DD and elucidated its underlying mechanisms. Using a DD mouse model induced by high‐fat diet, streptozotocin, and chronic unpredictable mild stress, we administered FCE at varying doses and employed a multimodal approach including behavioral tests, biochemical assays, UPLC‐MS/MS, network pharmacology, molecular docking, molecular dynamics simulation, immunofluorescence, Western blotting, and cellular validation. The results showed that FCE significantly reversed weight loss, reduced fasting blood glucose, and ameliorated depressive‐like behaviors. It also restored 5‐HT, DA, NE, and BDNF, lowered glutamate and pro‐inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α), and increased anti‐inflammatory IL‐10. UPLC‐MS/MS analysis identified 34 serum‐absorbed bioactive constituents, and integrated analyses highlighted neohesperidin (NH) and SRC as a candidate active constituent‐target axis. FCE suppressed pancreatic SRC overactivation, improved pancreatic and brain insulin (INS) related signaling, and these molecular changes were associated with behavioral recovery. In vivo pharmacodynamic validation further showed that NH partially reproduced the metabolic, behavioral, and biochemical effects of FCE in DD mice. In high‐glucose‐induced MIN6 cells, NH enhanced insulin secretion, mitigated reactive oxygen species accumulation, and restored mitochondrial membrane potential, whereas these protective effects were markedly attenuated after SRC knockdown. Collectively, these findings suggest that FCE ameliorates DD, at least in part, through NH/SRC‐mediated regulation of insulin signaling and neuroinflammation, supporting its potential as a multi‐target natural therapeutic candidate for DD.