{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:00:58Z","timestamp":1788843658858,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/National Cancer Institute Physical Sciences\u2013Oncology Network Award","award":["1R01CA227493"],"award-info":[{"award-number":["1R01CA227493"]}]},{"name":"Live Like Bella Pediatric Cancer Research Initiative","award":["9LA08"],"award-info":[{"award-number":["9LA08"]}]},{"name":"Live Like Bella Pediatric Cancer Research Initiative Program of the Florida Department of Health","award":["23L12"],"award-info":[{"award-number":["23L12"]}]},{"name":"U.S. Department of Defense Congressionally Directed Medical Research Kidney Cancer Research Programs","award":["KC210133"],"award-info":[{"award-number":["KC210133"]}]},{"name":"University of Miami Sylvester Comprehensive Cancer Center Developmental Stanley J. Glaser Foundation Grant","award":["UM SJG 2023-01"],"award-info":[{"award-number":["UM SJG 2023-01"]}]},{"name":"Sylvester Tumor Biology Intraprogrammatic Award","award":["TB-INTRA-2024-03"],"award-info":[{"award-number":["TB-INTRA-2024-03"]}]},{"name":"Women\u2019s Cancer Association FY2025 Award"},{"name":"Veterans Administration Merit Review Award","award":["BX-24-001"],"award-info":[{"award-number":["BX-24-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in podocyte injury. This study investigated the role of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a podocyte-enriched lipid-modulating enzyme, in radiation- and cisplatin-induced nephrotoxicity. Using a doxycycline-inducible, podocyte-specific SMPDL3B transgenic mouse model, renal injury was assessed following focal kidney irradiation, cisplatin administration, or their combination through functional assays, histopathology, ultrastructural analysis, immunofluorescence, and targeted lipidomics. Combined radiation and cisplatin exposure markedly reduced podocyte SMPDL3B expression, accompanied by podocyte depletion, glomerular basement membrane remodeling, proteinuria, and impaired renal function. These structural and functional abnormalities were associated with the selective accumulation of long-chain ceramide-1-phosphate species. In contrast, podocyte-specific induction of SMPDL3B preserved glomerular architecture, maintained renal function, and prevented pathological ceramide-1-phosphate elevation. Collectively, these findings identify SMPDL3B as a key regulator of podocyte stability and lipid homeostasis during chemoradiation stress. Enhancing SMPDL3B activity may represent a mechanistically grounded strategy to mitigate treatment-induced kidney injury while preserving anticancer efficacy.<\/jats:p>","DOI":"10.3390\/cells15020205","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T13:55:34Z","timestamp":1769176534000},"page":"205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting SMPDL3B to Ameliorate Radiation- and Cisplatin-Induced Renal Toxicity"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9820-2126","authenticated-orcid":false,"given":"Anis","family":"Ahmad","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamroop Kumar","family":"Mallela","sequence":"additional","affiliation":[{"name":"Katz Family Division of Nephrology and Hypertension, Department of Medicine, and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Alnukhali","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4757-7494","authenticated-orcid":false,"given":"Sandra","family":"Merscher","sequence":"additional","affiliation":[{"name":"Katz Family Division of Nephrology and Hypertension, Department of Medicine, and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5065-9522","authenticated-orcid":false,"given":"Alla","family":"Mitrofanova","sequence":"additional","affiliation":[{"name":"Katz Family Division of Nephrology and Hypertension, Department of Medicine, and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef H.","family":"Zeidan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"},{"name":"Department of Radiation Oncology Baptist Health, Lynn Cancer Institute, Boca Raton, FL 33437, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Pollack","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Fornoni","sequence":"additional","affiliation":[{"name":"Katz Family Division of Nephrology and Hypertension, Department of Medicine, and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8684-4372","authenticated-orcid":false,"given":"Brian","family":"Marples","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"},{"name":"Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Ave. Box 647, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1200\/JCO-24-02534","article-title":"Nephrotoxicity Surveillance for Childhood and Young Adult Survivors of Cancer: Recommendations From the International Late Effects of Childhood Cancer Guideline Harmonization Group","volume":"43","author":"Kooijmans","year":"2025","journal-title":"J. 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