Background:&nbsp;Sepsis is characterized by a dysregulated host response, in which monocytes are pivotal drivers of systemic hyperinflammation and lethal organ dysfunction. There is an urgent clinical need to identify distinct clinical signatures for early patient stratification and to uncover novel therapeutic targets.<br><br>Methods:&nbsp;We analysed potassium channel KCNJ2&nbsp;(encoding Kir2.1) expression in clinical cohorts of patients with sepsis, mild infection, and healthy controls to evaluate its diagnostic and prognostic value. Using monocyte-specific Kcnj2&nbsp;knockout mice, we investigated the role and mechanism of Kir2.1 in sepsis pathogenesis through single-cell transcriptomics and lipidomics. The cecal ligation and puncture model and the Klebsiella pneumoniae&nbsp;infection model were employed to assess the therapeutic efficacy of the Kir2.1 inhibitor ML133.<br><br>Findings:&nbsp;Monocytic KCNJ2&nbsp;expression was significantly upregulated in patients with sepsis, effectively discriminating sepsis from mild infection and healthy states, and strongly predicting 28-day mortality. Knockout of monocytic Kcnj2&nbsp;in vivo&nbsp;significantly alleviated sepsis-induced inflammatory storm and organ injury. Mechanistically, monocytic Kir2.1 functions as a critical amplifier of hyperinflammation by facilitating calcium influx to upregulate the scavenger receptor CD36, which promotes pathological lipid accumulation and peroxidation, leading to mitochondrial damage and subsequent activation of the cGAS-STING inflammatory pathway. Pharmacological inhibition of Kir2.1 with ML133 significantly alleviated systemic inflammation and septic injury in both the CLP model and Klebsiella pneumoniae infection.<br><br>Interpretation:&nbsp;Our work establishes monocytic KCNJ2 as a distinct clinical signature and a potential therapeutic target for sepsis, highlighting the Kir2.1-CD36-cGAS-STING axis as a key pathogenic mechanism amenable to pharmacological intervention.