Dehydrocostus lactone attenuates sepsis-associated neuroinflammation by directly targeting JAK2 identified through thermal proteome profiling.

Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis characterized by uncontrolled neuroinflammation. Dehydrocostus lactone (DL), a bioactive sesquiterpene lactone derived from Aucklandia lappa Decne., exhibits anti-inflammatory properties; however, its molecular targets in SAE remain unclear. Here, we investigated the protective effects and target mechanism of DL on CLP-induced septic mice and LPS-stimulated BV2 microglia. DL improved survival, attenuated brain injury, reduced inflammatory cytokine production, and restored microglial polarization homeostasis. Transcriptomic analysis revealed significant regulation of inflammatory pathways following DL treatment, while thermal proteome profiling (TPP) coupled with DIA-MS identified JAK2 as a candidate target of DL. Further validation by CETSA, SPR, molecular docking, and molecular dynamics simulations confirmed direct DL-JAK2 interaction. Mechanistically, DL suppressed JAK2 phosphorylation and downstream STAT3 activation, thereby inhibiting neuroinflammatory responses. These findings establish JAK2 as a direct pharmacological target of DL and support its potential as a candidate intervention for SAE-associated neuroinflammatory injury.