Natural products targeting TGF-β/Smad signaling in renal fibrosis: Multiomics-based novel molecular mechanisms and therapeutic strategies.

BACKGROUND: Renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) have become one of the major global public health challenges. Regardless of the underlying aetiology, renal fibrosis is a common pathological endpoint in the progression of diverse kidney diseases to end-stage renal disease. Increasing studies have highlighted that emerging multi-omics techniques (metagenomics, transcriptomics, proteomics and metabolomics) have been used for elucidating the pathogenesis of kidney disease and underlying molecular mechanism of renal fibrosis. However, few reviews provide a comprehensive and systematic presentation of multi-omics signaling-mediated TGF-β/Smad pathway in both AKI and CKD as well as therapeutic strategies for targeting signaling cascades by natural products.

PURPOSE AND STUDY DESIGN: This review summarizes multi-omics signaling-mediated TGF-β/Smad pathway and therapeutic strategies of natural products by targeting this signaling axis in patients and animal models with kidney disease.

METHODS: All the available information is searched by several electronic database such as Web of Science, Pubmed, ScienceDirect, Splinker, Google Scholar, etc., that covered approximately 1000 publications from 2015 to 2025.

RESULTS: Ample evidence has indicated that transforming growth factor-β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling pathway plays a central role in renal fibrosis. Based on the multi-omics techniques, a variety of novel mediators are identified and affects kidney diseases by regulating TGF-β/Smad pathway. Therefore, targeting TGF-β/Smad pathway is an important and promising antifibrotic therapy. This review summarizes TGF-β/Smad pathway in both AKI and CKD, elaborate on the multidimensional regulatory mechanisms in renal fibrosis by crosstalk between TGF-β/Smad pathway and novel multi-omics signaling-associated mechanisms including microbial dysbiosis, dysregulating non-coding ribonucleic acids including long non-coding RNAs and microRNAs and metabolite disorder and shed light on the latest therapeutic effects of natural products such as terpenoids, anthraquinones, xanthones and flavonoids as well as natural polysaccharides by targeting multi-omics signaling-mediated TGF-β/Smad pathway.

CONCLUSION: This review presents a multiomics-driven therapeutic strategy for the development of effective and precise antifibrotic therapies.