Potential Involvement of PI3K/AKT Signaling Pathway in the Protective Effects of Rhinacanthus nasutus Against Diabetic Nephropathy-Induced Oxidative Stress

Oxidative stress is a primary driver of diabetic nephropathy (DN), highlighting the urgent need for potent natural antioxidants. This study explored the reno-protective potential and associated mechanisms of Rhinacanthus nasutus aqueous extract (AE). Phytochemical profiling via Q Exactive HF Orbitrap LC–MS/MS and serum pharmacochemistry analysis identified 38 constituents, among which 25 bioavailable constituents (e.g., caffeic acid and naringenin) might be the key bioactive ones. In the L6 myotubes in vitro assays, AE (75 μg/mL) was observed to upregulate the PI3K/AKT and GLUT4 signaling cytokines, coinciding with enhanced glucose uptake, as confirmed by Western blot with insulin as a positive control. Furthermore, in STZ-induced DN rats, AE could reduce MDA levels (0.58 vs. 1.44 nmol/mgprot) and restore T-SOD, CAT, and GSH-Px levels (170.57, 51.93, 63.68 vs. 114.93, 40.84, 50.99 mgprot). The protective effects were accompanied by the modulation of PI3K/AKT/mTOR signaling axis. These findings suggest that AE exerts dual efficacy involving glucose uptake regulation and oxidative stress inhibition. Consequently, Rhinacanthus nasutus represents a promising natural antioxidant resource with potential for the management of DN.