Hippocampal LANCL1 attenuates postoperative cognitive dysfunction via the SIRT1/PGC-1α-mediated mitochondrial...

Postoperative cognitive dysfunction (POCD) is a prevalent and clinically significant complication in elderly surgical patients, yet effective therapeutic interventions remain scarce. Mitochondrial dysfunction, particularly impaired biogenesis, has been implicated as a central mechanism. LANCL1 is known for its neuroprotective properties against oxidative stress, but its role in POCD has not been explored. Here, we observed marked downregulation of LANCL1 in the hippocampi of aged mice following surgical trauma, correlating with cognitive decline and neuronal damage. Hippocampal-specific overexpression of Lancl1 via lentiviral vector significantly ameliorated cognitive deficits, including novel object recognition impairment, reduced neuronal injury, restored mitochondrial ultrastructure. Moreover, LANCL1 overexpression increased hippocampal ATP content and elevated the ratios of mitochondrial DNA-encoded genes (16S rRNA and ND1) relative to the nuclear gene HK2, indicating enhanced mitochondrial biogenesis. Histological analyses further revealed increased neuronal survival in the CA1 and CA3 subfields. Single-cell sequencing data demonstrated that LANCL1 expression in neurons was specifically reduced after LPS challenge compared to saline controls, supporting its vulnerability to inflammatory stress. LANCL1 overexpression also reduced hippocampal MDA levels and restored SOD activity, mitigating oxidative stress. Mechanistically, LANCL1 overexpression was associated with upregulation of the SIRT1/PGC-1α signaling axis and its downstream transcription factors NRF1 and TFAM essential for mitochondrial biogenesis. Importantly, co-administration of the SIRT1-specific inhibitor EX-527 completely abolished the protective effects of LANCL1, including the restoration of ATP levels, mtDNA copy number, neuronal survival, and cognitive performance, demonstrating that SIRT1 activity is required for LANCL1-mediated protection. Collectively, these findings establish LANCL1 as a critical regulator of mitochondrial health in the postoperative brain and highlight its therapeutic potential for mitigating POCD via enhancing SIRT1/PGC-1α-mediated mitochondrial biogenesis.