SIRT1 alleviates anxiety and depression in asthmatic mice by reducing H4K12 lactylation to attenuate microglial oxidative stress

This study aimed to investigate whether the SIRT1/H4K12 Lactylation/HIF-1α axis in hippocampal microglia drives anxiety‑ and depression‑like behaviors through oxidative stress in an asthmatic mouse model, and to elucidate the underlying regulatory mechanisms. An ovalbumin (OVA)-induced asthmatic mouse model was established. Anxiety- and depression-like behaviors were assessed by open field test (OFT), tail suspension test (TST), and forced swim test (FST). Microglial oxidative stress was evaluated using BODIPY C11, DHE staining, transmission electron microscopy (TEM), and assays for superoxide dismutase (SOD), malondialdehyde (MDA), and 8-hydroxy-2’-deoxyguanosine (8-OHdG). RNA sequencing, western blotting, immunofluorescence, and Cleavage Under Targets and Tagmentation (CUT&Tag) analyses were employed to identify the SIRT1/H4K12lac/HIF-1α axis. Functional validation was performed using pharmacological interventions (SRT2104/EX527), myeloid cell-specific SIRT1 conditional knockout mice, adeno-associated virus (AAV)-mediated microglia-targeted gene manipulation, and an LPS-induced BV2 cell model. A brain-targeted nano-system was constructed by loading SRT2104 into recombinant human heavy-chain ferritin (rHF) to achieve synergistic ROS scavenging. Asthmatic mice exhibited significant hippocampal-dependent anxiety- and depression-like behaviors that positively correlated with microglial activation. These microglia displayed pronounced oxidative stress and a distinct epigenetic signature characterized by SIRT1 downregulation and H4K12 Lactylation (H4K12lac) upregulation. Bidirectional modulation of this axis pharmacologically or genetically controlled microglial oxidative stress, neuroinflammation, and behavioral phenotypes. CUT&Tag analysis identified HIF-1α as a key downstream target. The rHF-SRT2104 nano-system achieved efficient brain delivery and synergistic ROS clearance, outperforming free SRT2104 in reversing pathological phenotypes. Asthma disrupts the microglial SIRT1/H4K12lac/HIF-1α axis, triggering ROS-driven oxidative stress and neuroinflammation that ultimately lead to anxiety- and depression-like behaviors. This study reveals a novel oxidative stress-centric mechanism for the “lung-brain axis” and provides a brain-targeted nano-therapeutic strategy with translational potential for asthma-related neuropsychiatric comorbidities. Not applicable.