Clostridium perfringens alpha toxin (CPA), a zinc-dependent phospholipase C, is a key virulence factor in gas gangrene. While its membrane-disrupting cytotoxicity is well characterized, its capacity to modulate neutrophil function and promote pathological inflammation is poorly defined. Here, we show that CPA induces neutrophil extracellular trap (NETs) formation by mobilizing and functionally reprogramming immature neutrophils. In a murine model, CPA challenge caused dose-dependent mortality and multi-organ injury, driven by a dramatic expansion of a pro-NETotic immature neutrophil subset identified by single-cell RNA sequencing. This was confirmed by elevated systemic NETs markers and extensive NETs deposition in damaged tissues. Mechanistically, CPA directly triggered reactive oxygen species (ROS)-dependent, peptidylarginine deiminase 4 (PAD4)-mediated NETosis in both murine and human neutrophils, revealing a conserved pathogenic mechanism. Importantly, therapeutic targeting of the NETotic pathway—via PAD4 inhibition, (Deoxyribonuclease I) DNase I treatment, or neutrophil depletion—significantly reduced tissue damage and improved survival. These findings identify a CPA–neutrophil–NETs axis as a central driver of immunopathology. Our study reframes CPA from a classical cytolysin to a potent immunomodulatory toxin that hijacks neutrophil fate. Our findings validate the NETotic pathway as a critical therapeutic target, providing a strong rationale for developing host-directed therapies—potentially in combination with toxin-neutralizing agents—to combat severe toxin-driven diseases.
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