Seco-tanapartholide B ameliorates acute lung injury by covalently activating PKM2 and reprogramming glycolytic metabolism.

Acute lung injury (ALI) is a life-threatening inflammatory condition with limited therapeutic options. Metabolic reprogramming, particularly PKM2-mediated glycolysis, plays a pivotal role in inflammatory responses, yet natural activators targeting this pathway remain largely unexplored. Herein, we found that seco-tanapartholide B (SB), a sesquiterpene lactone derived from the medicinal and edible herb Artemisia argyi, suppresses inflammation and glycolysis both in vitro and in vivo, thereby alleviating lipopolysaccharide (LPS)-induced ALI. Using thermal proteome profiling (TPP), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and bio-layer interferometry (BLI), we identified PKM2 as the direct molecular target of SB. LC-MS/MS analysis further revealed that SB covalently binds to Cys424 of PKM2 through its α-methylene-γ-lactone moiety, leading to enhanced pyruvate kinase activity and promoted PKM2 tetramerization. Consequently, this modification suppressed glycolysis as well as inflammation-related pathways, including NF-κB and STAT3 signaling, and reduced HIF-1α expression. Additionally, genetic knockdown of PKM2 attenuates the anti-inflammatory and glycolysis-inhibitory effects of SB in macrophages. Collectively, these findings identify SB as a natural PKM2 activator that therapeutically targets metabolic-inflammatory crosstalk in ALI. This study extends the potential application of PKM2 activators beyond oncology to inflammatory lung diseases and provides a biochemical rationale for promoting PKM2 tetramerization as a therapeutic strategy for ALI/acute respiratory distress syndrome (ARDS).