Diabetes mellitus is a multifactorial metabolic disorder driven by dysregulated signaling networks, and its complications are closely associated with insulin resistance, metabolic imbalance, oxidative stress, chronic inflammation, mitochondrial dysfunction, and disturbed cell-fate control. Astragaloside IV (AS-IV), a major bioactive saponin derived from Astragalus membranaceus, has attracted increasing attention as a multi-target candidate for diabetes and diabetes-related complications. This review summarizes recent advances in the signaling pathway-mediated anti-diabetic mechanisms of AS-IV, with particular emphasis on the integrated regulation of PI3K/Akt, AMPK, NF-κB, Nrf2/HO-1, mTOR, MAPK, and cell-fate-related pathways. Current evidence indicates that AS-IV improves insulin sensitivity and glucose metabolism through PI3K/Akt activation, regulates energy and lipid metabolism via AMPK-related signaling, suppresses inflammatory amplification by inhibiting NF-κB and NLRP3 inflammasome activation, and alleviates oxidative injury through activation of the Nrf2/HO-1 antioxidant axis. In addition, AS-IV modulates autophagy, apoptosis, ferroptosis, and mitochondrial homeostasis, thereby contributing to organ protection in diabetic kidney disease, cardiovascular complications, retinopathy, neuropathy, and diabetic foot ulcers. Compared with previous reports that mainly focused on isolated pathways or single complications, this review highlights a network-level and multi-pathway integration perspective, emphasizing the cross-talk among metabolic regulation, inflammation, oxidative stress, mitochondrial function, and programmed cell fate. Nevertheless, most current evidence remains derived from preclinical models, and important translational barriers, including low bioavailability, heterogeneous dosing regimens, insufficient pharmacokinetic-pharmacodynamic data, and limited clinical validation, still need to be addressed. Future studies integrating standardized disease models, multi-omics strategies, clinical samples, and well-designed prospective trials are required to clarify the therapeutic positioning of AS-IV and facilitate its translation as a potential multi-target agent for diabetes therapy.
