{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:04:54Z","timestamp":1790597094295,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002767","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2020JJ4778"],"award-info":[{"award-number":["2020JJ4778"]}],"id":[{"id":"10.13039\/501100002767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002767","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2024JJ5464"],"award-info":[{"award-number":["2024JJ5464"]}],"id":[{"id":"10.13039\/501100002767","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Changsha","award":["kq2402239"],"award-info":[{"award-number":["kq2402239"]}]},{"DOI":"10.13039\/501100002822","name":"Graduate Research and Innovation Project of Central South University","doi-asserted-by":"publisher","award":["1053320251796"],"award-info":[{"award-number":["1053320251796"]}],"id":[{"id":"10.13039\/501100002822","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002822","name":"Graduate Research and Innovation Project of Central South University","doi-asserted-by":"publisher","award":["1053320222414"],"award-info":[{"award-number":["1053320222414"]}],"id":[{"id":"10.13039\/501100002822","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1053320251796"],"award-info":[{"award-number":["1053320251796"]}],"id":[{"id":"https:\/\/ror.org\/00f1zfq44","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1053320222414"],"award-info":[{"award-number":["1053320222414"]}],"id":[{"id":"https:\/\/ror.org\/00f1zfq44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Diabetic kidney disease (DKD) is a progressive nephropathy associated with excessive pyroptosis and ferroptosis. Impaired renal mitophagy has been implicated in inflammation and lipid peroxidation in DKD; however, it remains unclear whether and how it modulates pyroptosis and ferroptosis. Punicalagin (PU), a natural polyphenol with potent anti-inflammatory and antioxidant activities, has been shown to improve DKD, yet its underlying mechanism requires further elucidation. This study aimed to investigate whether PU alleviates pyroptosis- and ferroptosis-related indicators in diabetes-associated renal injury in association with SESN2-related mitophagy, using both in vivo and in vitro models. Methods: We established a diabetic mouse model using a high-fat diet and streptozotocin (STZ) injection. After successful modeling, we measured serum blood urea nitrogen (BUN) and creatinine (CREA), and stained renal tissues with HE, Masson, and PASM for pathological scoring. Protein expression of kidney injury molecule-1 (KIM-1), pyroptosis-related (caspase-1, IL-18), ferroptosis-related (FTH1, ACSL4), mitophagy-related (PINK1, Parkin, p62, LC3-II\/I), and SESN2 were quantified by Western blotting. In high-glucose-induced HK-2 cells, glucose uptake was assessed by 2-NBDG, pyroptotic\/ferroptotic morphology by electron microscopy, and TOM20\/LC3 co-localization by confocal microscopy. Furthermore, Mitochondrial Division Inhibitor 1 (Mdivi-1) was used to probe the potential involvement of mitophagy in the effects of PU on pyroptosis- and ferroptosis-related markers, and transfection of SESN2 siRNA was used to investigate whether the effects of PU on mitophagy-related signaling are associated with SESN2 expression. Results: Diabetic mice exhibited renal histological abnormalities, elevated BUN\/CREA, and increased KIM-1 expression. Additionally, pyroptosis- and ferroptosis-related proteins were dysregulated, while mitophagy-related proteins and SESN2 were downregulated. PU treatment significantly reversed these abnormalities, which were confirmed in high-glucose-treated HK-2 cells. In the high-glucose-induced HK-2 cell model, treatment with Mdivi-1 attenuated the effects of PU on pyroptosis- and ferroptosis-related markers. In parallel, knockdown of SESN2 by siRNA partially reversed the PU-induced changes in mitophagy-related protein expression. Conclusions: PU may modulate mitophagy-related signaling in association with SESN2, accompanied by changes in pyroptosis- and ferroptosis-related markers in diabetes-associated renal injury. This study provides preliminary evidence for the renoprotective effect of PU against DKD, potentially involving SESN2-related mitophagy and the concurrent regulation of pyroptosis- and ferroptosis-related markers in renal cells. Collectively, PU warrants further investigation as a candidate compound for DKD.<\/jats:p>","DOI":"10.3390\/nu18193192","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"3192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Punicalagin Alleviates Diabetic Kidney Injury: Potential Involvement of SESN2-Related Mitophagy and Changes in Pyroptosis-\/Ferroptosis-Related Indicators"],"prefix":"10.3390","volume":"18","author":[{"given":"Yue","family":"Huang","sequence":"first","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Jiazhen","family":"He","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yizhen","family":"Ma","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Ziyi","family":"You","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yuhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Rou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Xiuying","family":"Tan","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-3344","authenticated-orcid":false,"given":"Lina","family":"Yang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"ref_1","unstructured":"International Diabetes Federation (2023). 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