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Here, a zebrafish embryonic amoxicillin exposure (EAE) model was used to quantify dose\u2010 and time\u2010dependent developmental outcomes and to elucidate underlying metabolic\u2013epigenetic mechanisms. EAE induced dose\u2010 and time\u2010dependent increases in mortality and malformation rates, and significantly impaired differentiation of liver, interrenal gland, heart and brain, accompanied by mitochondrial structural damage and reduction in ATP levels. Multi\u2010omics integration identified a previously uncharacterized long noncoding RNA, PCALRx, which was associated with pyruvate carboxylase (PC) and negatively regulated PC protein stability. PCALRx promoted ubiquitination\u2010mediated degradation of PC, resulting in impaired mitochondrial metabolic function and subsequent multi\u2010organ differentiation defects. Knockdown of PCALRx mitigated mitochondrial dysfunction and improved EAE\u2010induced developmental defects. Finally, a drug\u2010repurposing strategy nominated thiamine (vitamin B1) as a metabolic modulator capable of mitigating EAE\u2010induced developmental changes in zebrafish larvae. This protective effect was further validated in a mouse model of prenatal amoxicillin exposure. Together, these findings reveal an lncRNA\u2010mediated regulatory mechanism involving PC ubiquitination and mitochondrial metabolic disruption in amoxicillin\u2010associated developmental toxicity and provide a potential intervention strategy relevant to environmental amoxicillin exposure.<\/jats:p>","DOI":"10.1002\/advs.76937","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:05:47Z","timestamp":1785935147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long Noncoding RNA PCALRx Interacts with Pyruvate Carboxylase to Drive Multi\u2010Organ Developmental Toxicity in Zebrafish Embryos Exposed to Amoxicillin"],"prefix":"10.1002","author":[{"given":"Yixue","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Pharmacology Wuhan University Taikang School of Medicine (School of Basic Medical Sciences)  Wuhan 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