Targeting HIF-1α rescues microglial efferocytosis via the SLC7A11-TAM pathway to ameliorate Sepsis-associated...

Sepsis-associated encephalopathy (SAE) is a common and debilitating complication of sepsis, yet its cellular mechanisms and targeted therapies remain unclear. Microglia preserve neuroinflammatory homeostasis and neural circuit integrity through efferocytosis, but how this process is altered in SAE and regulated by immunometabolism is poorly defined. Here, we investigated the molecular basis of microglial efferocytosis impairment using LPS-stimulated BV2 cells and a cecal ligation and puncture (CLP) murine SAE model. We integrated RNA sequencing, HIF-1α and SLC7A11 gain- and loss-of-function approaches and in vitro functional assays. In vivo, HIF-1α was pharmacologically inhibited (KC7F2) or stabilized (DMOG) to evaluate its role in SAE. We assessed microglial efferocytosis and polarization, neuronal and synaptic integrity, cognition, survival, and brain metabolomics. LPS induced a pro-inflammatory microglial phenotype and reduced efferocytosis mediators (Tyro3, Mertk, Axl), impairing clearance of apoptotic neurons. HIF-1α upregulation interacted with SLC7A11 to suppress the TAM-Rac1-NCKAP1 axis, leading to efferocytic failure; knockdown of HIF-1α or SLC7A11 restored efferocytosis. In CLP mice, HIF-1α/SLC7A11 elevation coincided with TAM-Rac1-NCKAP1 suppression. These results reveal that impaired microglial efferocytosis is a key but overlooked feature in SAE. KC7F2 restored efferocytosis, shifted cytokines toward anti-inflammatory profiles, improved cognition and survival, and normalized metabolomic signatures, while DMOG produced opposite effects. This work uncovers a previously unknown HIF-1α-SLC7A11 pathway driving microglial dysfunction in SAE, offering fresh insight into disease mechanisms and pointing to HIF-1α as a promising therapeutic target.