{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:56:43Z","timestamp":1790866603296,"version":"4.1.0"},"reference-count":198,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008402","name":"Chengdu University of Traditional Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dysregulated mitochondrial dynamics, including fission, fusion, biogenesis, and mitophagy, underlie the pathogenesis of many diseases. Natural products have the potential for multi-target therapy, but insufficient understanding of their mechanisms of action and pharmacokinetic limitations hinder their clinical translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This review proposes a regulatory framework covering the four dimensions of biogenesis, morphology, quality control, and defense, aiming to systematically clarify how natural products regulate mitochondrial function and critically evaluate their translational potential. The framework emphasizes that inter-organelle contact platforms, such as mitochondria\u2013endoplasmic reticulum contact sites (MERCs) and mitochondrial\u2013lysosomal contact sites (MLCs), are key sites through which natural products exert regulatory effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Major scientific databases, including PubMed, Web of Science, and Scopus, were searched, and evidence on mechanisms, pharmacokinetics, and toxicology from preclinical and clinical studies was comprehensively reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Natural products can selectively regulate key mitochondrial pathways and regulatory nodes, including the AMPK\/SIRT1\/PGC-1\u03b1 axis involved in mitochondrial biogenesis, the DRP1 axis involved in mitochondrial fission, and the PINK1\/Parkin pathway involved in mitophagy. Representative metabolites include resveratrol, curcumin, and\n                      <jats:italic>Coptis chinensis<\/jats:italic>\n                      -derived alkaloids. A key finding of this review is that the intestinal microbiota plays an important role in converting low-bioavailability precursors, such as tannins, into systemically active metabolites, such as urolithin A (UA), thus inducing mitophagy. Although these metabolites usually show strong activity\n                      <jats:italic>in vitro<\/jats:italic>\n                      , their low oral bioavailability and rapid metabolism lead to significant pharmacokinetic\/pharmacodynamic (PK\/PD) mismatch, which remains a major obstacle to their clinical translation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Natural products are powerful multidimensional regulators of mitochondrial homeostasis. In order to fully realize their therapeutic potential, strategies must be adopted to overcome PK\/PD mismatch, including the development of targeted delivery systems, in-depth analysis of microbiome\u2013metabolite interactions, and the integration of artificial intelligence and CRISPR-based technological innovation to support precision therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1911495","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:38:10Z","timestamp":1789709890000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhi-Yun","family":"Xiang","sequence":"first","affiliation":[{"name":"Chengdu Xinjin District Hospital of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu-Hua","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Deyang Sixth People\u2019s Hospital","place":["Deyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Ying","family":"Lan","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Huang","sequence":"additional","affiliation":[{"name":"Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Affiliated Meishan Hospital of Chengdu University of Traditional Chinese Medicine \/ Traditional Chinese Medicine Hospital of Meishan","place":["Meishan, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45208","DOI":"10.1021\/acsomega.3c06547","article-title":"DRP1: at the crossroads of dysregulated mitochondrial dynamics and altered cell signaling in cancer cells","volume":"8","author":"Adhikary","year":"2023","journal-title":"ACS Omega"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/561971","article-title":"Caffeic acid phenethyl ester as a protective agent against nephrotoxicity and\/or oxidative kidney damage: a detailed systematic review","volume":"2014","author":"Akyol","year":"2014","journal-title":"Sci. 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