Targeting AARS1-dependent lactylation improves neuronal process plasticity and mitigates cognitive deficits in...

Sepsis-associated encephalopathy (SAE) is a frequent and severe neurological complication of systemic infection, strongly associated with long-term cognitive impairment.¹ Despite its clinical significance, no targeted therapies are currently available. In this study, we established a murine model of sepsis using cecal ligation and puncture (CLP) and identified a metabolic pathway in which lactate accumulation drives neuronal process injury through aberrant activation of the ATRIP-ATR signaling axis. During sepsis, AARS1-the primary lactyltransferase responsible for lactylation in neuronal processes-catalyzes the lactylation of ATRIP at lysine 127 (K127), triggering ATRIP-ATR complex formation and pathway activation independent of DNA damage. This non-canonical signaling cascade promotes excessive autophagy, leading to synaptic dysfunction, neuronal process injury, and behavioral deficits. Notably, we found that L-alanine, a natural amino acid and endogenous substrate of AARS1, competitively inhibits lactate binding to AARS1, thereby suppressing ATRIP lactylation and downstream signaling. Both pharmacological inhibition of ATR with AZD6738 and AARS1 blockade via L-alanine treatment restored neuronal process plasticity and alleviated cognitive and behavioral impairments in SAE mice. Given the prevalent disruption of lactate homeostasis in sepsis and the accumulation of lactate observed in various neurodegenerative conditions, the AARS1-mediated lactylation of ATRIP and the consequent activation of the ATR pathway represent a promising therapeutic target for preserving neuronal plasticity and cognitive function in SAE and potentially other lactate-related neurological disorders.