Ramulus Mori (Sangzhi) Alkaloids (SZ-A) exert a renoprotective effect by activating PGC-1α to mediate fatty acid oxidation and mitochondrial homeostasis

Background: Chronic kidney disease (CKD), especially when comorbid with diabetes, represents a significant global health burden with limited therapeutic options. Ramulus Mori (Sangzhi) Alkaloids (SZ-A) is a natural alkaloid formulation approved in China for type 2 diabetes management, but its potential renoprotective role remains largely unexplored.

Purpose: This study aimed to comprehensively investigate the renoprotective effects of SZ-A and elucidate the underlying molecular mechanisms, independent of its established hypoglycemic effects.

Methods: We employed a multi-omics and functional validation approach. An adenine-induced CKD rat model was used to evaluate the therapeutic efficacy of SZ-A. Integrated proteomic and transcriptomic analyses of kidney tissues were performed to identify critical pathways. Further in vitro and in vivo experiments, including dual-luciferase reporter assays, were conducted to validate the pharmacological mechanisms and identify the key bioactive component.

Results: SZ-A dose-dependently ameliorated renal dysfunction and pathological injury in CKD rats. Multi-omics integration revealed that SZ-A activates the PPAR signaling pathway and enhances mitochondrial fatty acid oxidation (FAO), thereby restoring mitochondrial homeostasis and reducing lipid accumulation. We identified DNJ as the principal bioactive component of SZ-A responsible for transcriptionally activating PGC-1α, a master regulator of mitochondrial bioenergetics and FAO.

Conclusion: Our findings unveil a novel PGC-1α/FAO axis through which SZ-A exerts its renal protective effects. This study repositions SZ-A as a promising therapeutic candidate for CKD, offering dual metabolic and organ-protective benefits.