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

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

  • Phytomedicine. 2025 Dec 26:150:157743. doi: 10.1016/j.phymed.2025.157743.
Jiawei Song 1,  Jun Ye 2,  Ning Sheng 2,  Shengyuan Xu 2,  Hongliang Wang 2,  Yanfang Yang 2,  Shan Chen 3,  Jinlan Zhang 2,  Yan Tang 4,  Xinhua Xiao 5,  Yuling Liu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050, PR China; Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, PR China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050, PR China.
  • 3 Beijing Wehand-Bio Pharmaceutical Co., Ltd., Beijing 100260, PR China.
  • 4 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, PR China. Electronic address: [email protected].
  • 5 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, PR China. Electronic address: [email protected].
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050, PR China. Electronic address: [email protected].
PMID: 41505916 DOI: 10.1016/j.phymed.2025.157743
Abstract

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.

Keywords

Chronic kidney disease; Fatty acid oxidation; Mitochondria; PGC-1α; SZ-A.

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