{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T06:12:29Z","timestamp":1788502349174,"version":"build-2803163510"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Nobiletin (NOB), a naturally occurring polymethoxyflavone enriched in Citri Reticulatae Pericarpium\u2014the dried peel of mature citrus fruit\u2014has attracted increasing attention because of its multi-target pharmacological activities. This study explored the protective effects of NOB on diabetic nephropathy (DN), with a focus on TP53-associated PANoptosis and TFEB-related lysosomal and energy metabolic changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Forty male db\/db mice were randomly assigned to the model, metformin, low-dose NOB (30 mg\/kg\/day), and high-dose NOB (60 mg\/kg\/day) groups, with 10 mice per group. Ten age-matched male db\/m mice served as non-diabetic controls. Treatments were administered by gavage for 8 weeks. Metabolic parameters, lipid profiles, inflammatory cytokines, renal function, histopathology, untargeted metabolomics, energy metabolites, network pharmacology, surface plasmon resonance (SPR), immunofluorescence, qPCR, and Western blot analyses were performed. Supplementary\n                      <jats:italic>in vitro<\/jats:italic>\n                      validation was performed in high-glucose-treated HK2 renal tubular epithelial cells with TP53 knockdown or overexpression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NOB treatment reduced FBG, OGTT-AUC, INS, HOMA-IR, GSP, TC, TG, and LDL-C while increasing HDL-C. High-dose NOB improved renal function, reduced IL-1\u03b2 and IL-6, and alleviated histological damage. Untargeted metabolomics suggested that NOB partially restored pathway-level changes related to oxidative phosphorylation, lysosomal function, fatty acid metabolism, and energy metabolism. Network pharmacology identified TP53 as a central candidate target, and SPR analysis suggested binding between NOB and TP53 protein. NOB treatment reduced TP53 signal, promoted TFEB nuclear localization, and suppressed pyroptosis-, apoptosis-, and necroptosis-related markers in diabetic kidneys. Representative HK2 Western blot experiments showed expression patterns consistent with attenuation of high-glucose-induced PANoptosis-related protein activation after TP53 knockdown and partial counteraction of the NOB-associated regulatory pattern after TP53 overexpression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>NOB ameliorated DN-related metabolic disturbance, inflammation, renal dysfunction, histological injury, and fibrosis. These protective effects were associated with reduced TP53 activation, restoration of TFEB-related lysosomal and energy metabolic status, and suppression of PANoptosis-related pathways. Supplementary HK2 cell experiments provided supportive, representative evidence for the involvement of TP53 in high-glucose-induced PANoptosis-related protein activation and in the regulatory effect of NOB. These findings suggest that NOB may be a promising natural compound for DN intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1816623","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:28:36Z","timestamp":1788499716000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Nobiletin ameliorates diabetic nephropathy by modulating TP53-associated PANoptosis: an experimental study"],"prefix":"10.3389","volume":"13","author":[{"given":"Biwei","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Public Health, North China University of Science and Technology","place":["Tangshan, China"]},{"name":"College of Traditional Chinese Medicine","place":["North China University of Science and Technology, Tangshan, China"]},{"name":"Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its 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