Synergy of intermittent fasting and ferroptosis inhibition dampens ‘cytokine storm’

Abstract Background: As a prototypic cytokine storm syndrome (CSS), secondary haemophagocytic lymphohistiocytosis (sHLH), or macrophage activation syndrome in the context of rheumatic disease, is characterized by profound hyperinflammation and multisystem dysfunction. Caloric restriction and intermittent fasting (IF) are known to ameliorate inflammatory response. However, their in vivo roles and mechanistic importance in CSS remain largely elusive. Herein, by using a Poly I:C and lipopolysaccharide sequential challenging HLH mice model, we explore the anti-inflammatory effect of IF.Findings: Compared to mice feeding with regular diet, IF treated HLH model showed improved survival and less systemic inflammation, as evidenced by alleviatived splenomegaly and acute lung injury and downregulated serum pro-inflammatory cytokines. Mechanistically, IF down-modulated glycolysis, the fueling process in cytokine storm. In addition, we underscored the relevance of ferroptosis, a special form of programmed cell death, to the HLH-related acute lung injury. Notably, combination of IF and ferroptosis inhibition synergistically provided robust protection against lethal HLH in mice. Conclusions: Our study revealed the nexus between hyperinflammation and tissue injury in cytokine storm, and highlighted that non-immunosuppressive metabolic modulations might have translational values in relevant diseases.