HMGB1 aggravates neuronal ferroptosis and microglial inflammation in metabolic syndrome-associated cognitive impairment via the NRF2-autophagic flux axis

Abstract

Metabolic syndrome (MetS)-associated cognitive impairment is a growing global health crisis. The hippocampus is particularly vulnerable to metabolic stress, yet the precise molecular mechanisms linking systemic metabolic dysfunction to cognitive decline remain unclear. High-mobility group box 1 (HMGB1), a damage-associated molecule, is elevated in MetS. However, its specific role in simultaneously regulating hippocampal neuronal ferroptosis and microglial activation is poorly defined. Here we show that HMGB1 exacerbates MetS-associated cognitive impairment by promoting both neuronal ferroptosis and microglial inflammation. Using a high-fat high-glucose diet mouse model and primary co-cultures, we found that HMGB1 neutralization alleviated cognitive deficits, reduced neuronal ferroptosis, and suppressed microglial activation. Mechanistically, extracellular HMGB1 acts through neuronal toll-like receptor 4 (TLR4) to trigger the ubiquitination and degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This HMGB1-induced loss of NRF2 impairs autophagic flux, thereby aggravating ferroptosis and neuroinflammation. Furthermore, in vitro conditioned medium experiments revealed a reciprocal pathological aggravation, where ferroptotic neurons and activated microglia both secrete HMGB1 to exacerbate each other's pathological state. These findings position HMGB1 as a pivotal mediator linking metabolic stress specifically to neuronal ferroptosis and neuroimmune activation. Targeting the HMGB1-NRF2-autophagic flux axis therefore offers a promising therapeutic strategy for mitigating cognitive impairment in patients with MetS.