Kisspeptin-54 attenuates acute lung injury in septic mice through AMPK-mediated suppression of NLRP3 inflammasome

In a mouse model of sepsis-induced acute lung injury, giving kisspeptin-54 improved survival and reduced lung damage, and in cultured lung macrophages it dampened the inflammatory NLRP3 inflammasome pathway. The protection depended on AMPK signaling, since blocking AMPK reversed the effect. This is a preclinical study and does not show whether kisspeptin would work in humans.

Journal article — Preclinical animal study with in vitro validation. Population: C57BL/6 mice with cecal ligation and puncture (CLP)-induced sepsis and MH-S mouse alveolar macrophages. Follow-up: 7-day survival assessment. Interventions: Kisspeptin-54; Compound C (AMPK inhibitor).

In CLP septic mice, circulating kisspeptin-54 and pulmonary GPR54 were reduced during sepsis. Exogenous kisspeptin-54 improved 7-day survival, lowered severity scores, and reduced peritoneal inflammatory infiltration, pulmonary vascular leakage and edema, and IL-1β/IL-18 levels. It also suppressed NLRP3, ASC and cleaved caspase-1 in lung tissue while enhancing AMPK phosphorylation, and AMPK inhibitor compound C reversed these effects. In MH-S cells, kisspeptin-54 reduced NLRP3 expression by 48% and cleaved caspase-1 maturation by 52%, with lower supernatant IL-1β. Baseline toxicity screening showed kisspeptin-54 alone was non-toxic in healthy animals and compound C alone did not worsen background septic mortality.

For researchers studying Kisspeptin, this paper extends its role beyond reproduction to a possible anti-inflammatory function in sepsis-associated lung injury. It proposes a specific mechanism—AMPK-mediated suppression of the NLRP3 inflammasome—and identifies neutrophils and alveolar macrophages as likely responding cells. It does not establish that kisspeptin-54 is safe or effective in humans, and the abstract provides no clinically actionable dose or regimen.

Key findings

In septic mice, circulating kisspeptin-54 was reduced and pulmonary GPR54 expression was downregulated compared with the non-septic state.
Exogenous kisspeptin-54 improved 7-day survival and lowered clinical severity scores in CLP mice.
Kisspeptin-54 attenuated lung injury, reducing peritoneal inflammatory infiltration, pulmonary vascular leakage and edema, and IL-1β and IL-18 levels.
Kisspeptin-54 enhanced AMPK phosphorylation and suppressed NLRP3, ASC and cleaved caspase-1; the AMPK inhibitor compound C reversed these protective effects.
In MH-S alveolar macrophages, kisspeptin-54 reduced NLRP3 expression by 48% and cleaved caspase-1 maturation by 52%, while also lowering supernatant IL-1β.
Kisspeptin-54 preferentially curbed pulmonary neutrophil accumulation over macrophages and was non-toxic in healthy animals at therapeutic doses.

Limitations

Mouse CLP model and cultured macrophage data may not translate to human sepsis.
No sample size or dose information is reported in the abstract, limiting appraisal of robustness.
Mechanistic evidence relies on a single AMPK inhibitor, compound C, which may have off-target effects.
Survival outcomes were assessed only over 7 days, so longer-term effects are not established.

The record

Journal: Neuropeptides 118: 102639
Published: 2026-06-23
PMID: 42418889 — DOI: 10.1016/j.npep.2026.102639
MeSH terms: Lung, Animals, Mice, Inbred C57BL, Mice, Sepsis, Male, Acute Lung Injury, AMP-Activated Protein Kinases, Inflammasomes, Kisspeptins, NLR Family, Pyrin Domain-Containing 3 Protein, Receptors, Kisspeptin-1
Funding: Huazhong University of Science and Technology
Author countries: China

Peptide profiles: Kisspeptin.

All indexed evidence: Kisspeptin trials & papers.