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The transforming growth factor-\u03b2 (TGF-\u03b2)\/suppressor of mothers against decapentaplegic (Smad) cascade governs key physiological events spanning cell proliferation, differentiation, immune homeostasis and extracellular matrix remodeling. Natural polysaccharides (NPs) are bioactive macromolecules widely distributed across diverse living organisms. This review summarizes the TGF-\u03b2\/Smad pathway, addresses NPs structure\u2013activity relationships, and dissects tissue-specific regulatory mechanisms. It highlights modulation of TGF-\u03b2\/Smad signaling by NPs via gut microbiota dysbiosis and metabolic disturbances under chronic injury. Targeting TGF-\u03b2\/Smad with NPs represents a promising therapeutic strategy for related chronic diseases. This review also discusses research bottlenecks and translational strategies, integrating gut microbiota\u2013metabolite crosstalk across multiorgan pathologies to advance mechanistic insights into NPs-driven tissue homeostasis restoration and support NPs-based targeted therapy development.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c11382","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:02:15Z","timestamp":1791453735000},"page":"32032-32055","source":"Crossref","is-referenced-by-count":0,"title":["Natural Polysaccharides\nin Health and Targeting TGF-\u03b2\/Smad\nSignaling Therapy in Chronic Diseases"],"prefix":"10.1021","volume":"74","author":[{"given":"Yun-Fei","family":"Wang","sequence":"first","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Bin","family":"Fang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Miao","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]},{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University , , ,","place":["Hangzhou, Zhejiang, China, 310003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]},{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University , , ,","place":["Hangzhou, Zhejiang, China, 310003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0239-7342","authenticated-orcid":true,"given":"Ying-Yong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , ,","place":["Hangzhou, China, 310053"]},{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University , , ,","place":["Hangzhou, Zhejiang, China, 310003"]},{"name":"First Medical Center of Chinese PLA General Hospital , , ,","place":["Beijing, China, 100853"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"issue":"10","key":"2026102109071792400_cit1","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1038\/s41565-025-02010-2","article-title":"Wearable biomolecular sensing nanotechnologies in chronic disease\nmanagement","volume":"20","author":"Tu","year":"2025","journal-title":"Nat. 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