{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:41:34Z","timestamp":1785865294404,"version":"3.56.0"},"reference-count":183,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and \u03b2-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols\u2014including hesperidin, naringenin, nobiletin, and tangeretin\u2014have emerged as promising agents capable of orchestrating a multi-targeted \u201cmetabolic reprogramming.\u201d These compounds modulate key signaling pathways, including AMPK, PI3K\/Akt, NF-\u03baB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve \u03b2-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance.<\/jats:p>","DOI":"10.3390\/medsci13030180","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T12:18:18Z","timestamp":1757074698000},"page":"180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic Reprogramming Through Polyphenol Networks: A Systems Approach to Metabolic Inflammation and Insulin Resistance"],"prefix":"10.3390","volume":"13","author":[{"given":"Shakila Jahan","family":"Shimu","sequence":"first","affiliation":[{"name":"Department of Health Informatics, Harrisburg University of Science and Technology, 326 Market St., Harrisburg, PA 17101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawad Ul Karim","family":"Mahir","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0030-3292","authenticated-orcid":false,"given":"Fardin Al Fahad","family":"Shakib","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arafath Amin","family":"Ridoy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratin Al","family":"Samir","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Jahan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3038-596X","authenticated-orcid":false,"given":"Md Fahim","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9065-200X","authenticated-orcid":false,"given":"Sadman","family":"Sazzad","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Informatics, Luddy School of Informatics, Computing and Engineering, Indiana University Indianapolis, 420 University Blvd, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1983-3435","authenticated-orcid":false,"given":"Shamima","family":"Akter","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes & Metabolism, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, 705 Maple Road, Williamsville, NY 14221, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1885-646X","authenticated-orcid":false,"given":"Mohammad Sarif","family":"Mohiuddin","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5065-9180","authenticated-orcid":false,"given":"Md Jalal Ahmed","family":"Shawon","sequence":"additional","affiliation":[{"name":"Department of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, Bernburger Strasse 55, 06366 K\u00f6then, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5176-3647","authenticated-orcid":false,"given":"Mohammad Hossain","family":"Shariare","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7910-7147","authenticated-orcid":false,"given":"Mohammad Mohabbulla","family":"Mohib","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"},{"name":"Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Magdeburger Str. 6, 06112 Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Borhan","family":"Uddin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Allocca, S., Monda, A., Messina, A., Casillo, M., Sapuppo, W., Monda, V., Polito, R., Di Maio, G., Monda, M., and La Marra, M. 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