{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:10:44Z","timestamp":1790143844983,"version":"4.0.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Acute kidney injury (AKI) converges on tubular epithelial cell (TEC) death and metabolic collapse, fueling the transition to chronic kidney disease (CKD), yet the molecular link between metabolic failure and inflammatory cell death remains poorly defined. Here, we integrated cross-model transcriptomics of three mechanistically distinct murine AKI models with single-cell RNA-seq, high-dimensional weighted gene co-expression network analysis, and machine learning feature selection. This multi-omics framework identified acyl-CoA synthetase medium-chain family member 2 (Acsm2), a rate-limiting mitochondrial enzyme for medium-chain fatty acid \u03b2-oxidation, as the top conserved hub gene suppressed in injured proximal tubule cells. Acsm2\/ACSM2A downregulation was confirmed in mouse AKI models and in human HK-2 cells subjected to oxygen\u2013glucose deprivation\/reperfusion (OGD\/R). ACSM2A deficiency alone was sufficient to simultaneously activate apoptosis, pyroptosis, and necroptosis, indicative of PANoptosis, whereas restoration of ACSM2A expression attenuated OGD\/R-induced cell death. Mechanistically,\n                    <jats:italic>ACSM2A<\/jats:italic>\n                    loss provoked mitochondrial oxidative stress and drove the accumulation of Z-form nucleic acids. Scavenging mitochondrial reactive oxygen species or silencing ZBP1 rescued cells from\n                    <jats:italic>ACSM2A<\/jats:italic>\n                    knockdown-induced cell death, implicating ZBP1 as a downstream mediator. Collectively, our findings establish\n                    <jats:italic>ACSM2A<\/jats:italic>\n                    loss as a trigger of ZBP1-dependent PANoptosis in TECs and position the ACSM2A\u2013ZBP1 axis as a candidate pathogenic mechanism that warrants further investigation as a potential therapeutic node for intercepting the AKI-to-CKD transition.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1936504","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:49:21Z","timestamp":1790142561000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration identifies Acsm2\/ACSM2A deficiency as a metabolic driver of ZBP1-mediated PANoptosis in acute kidney injury"],"prefix":"10.3389","volume":"14","author":[{"given":"Lijuan","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Nephrology, Nantong Rici Hospital Affiliated to Yangzhou University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Nantong Rici Hospital Affiliated to Yangzhou University","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"20086","DOI":"10.1074\/jbc.M117.806240","article-title":"A genome-wide screen in Escherichia coli reveals that ubiquinone is a key antioxidant for metabolism of long-chain fatty acids","volume":"292","author":"Agrawal","year":"2017","journal-title":"J. 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