Harnessing the Multi-Targeted Potential of Rehmanniae Radix Natural productsBioactives Against Renal Fibrosis: A Mechanistic Review

Keqin Zhao^1,2Han Zhu^2,3Liping Zheng^2,3Wenru Wang²Peng Liu^2*Ren-Huan Yu^2*Xiaobei Ma^2,4*

• ¹Institute of Basic Theory of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
• ²China Academy of Chinese Medical Sciences Xiyuan Hospital, Beijing, China
• ³Jiangxi University of Traditional Chinese Medicine, Nanchang, China
• ⁴Graduate School of China Academy of Chinese Medical Sciences, Beijing, China

Renal fibrosis represents the final common pathological pathway of nearly all chronic kidney disease (CKD), yet effective therapeutic options remain profoundly limited. Rehmanniae Radix, a botanical drugcornerstone herb in Traditional Chinese Medicine (TCM), has a long history of use for its nephroprotective properties. However, a systematic, mechanism-based understanding of how its natural productsindividual bioactive constituents combat renal fibrosis is conspicuously absent. Herein, we present the firsta comprehensive review to systematically dissect the multi-component, multi-target, and multi-pathway mechanisms through which the major active ingredients of Rehmanniae Radix ameliorate renal fibrosis. Our analysis reveals that these natural productscompounds, including Acteoside (also known as Verbascoside)Verbascoside, Catalpol, and Rehmannioside A, converge upon the inhibition of the canonical TGF-β1/Smad signaling pathway— a master regulator of fibrosis. This analysis focuses primarily on evidence from preclinical (in vivo and in vitro) models, as rigorous clinical data on the efficacy of these specific constituents remain limited. Furthermore, they exert potent anti-inflammatory and antioxidant effects via the modulation of pivotal signaling nodes such as NF-κB, Nrf2, and TLR4. Critically, this review illuminates unique and novel mechanisms, including the enhancement of autophagy by Acteoside and the targeted inhibition of the AT1R/MAPK14/IL-17 axis by Rehmannioside A in hypertensive nephropathy. By elucidating this intricate pharmacological network, this review not only decodes the scientific basis for the nephroprotective effectsefficacy of Rehmanniae Radix but also provides a robust theoretical foundation for the development of novel anti-fibrotic therapies and identifies promising molecular targets for future investigation.