At present, endotoxemia and sepsis are still causes of death in intensive care units, and the mortality of sepsis remains at around 30% (Goligorsky and Sun, 2020). Endotoxemia is sepsis caused by Lipopolysaccharide (LPS), characterized by cytokine storm and multiple organ dysfunction syndrome (Jang et al., 2021). A clinical study showed that 82% of septic shock patients presented with endotoxemia (Bottiroli et al., 2017). LPS is a major component of the outer membrane of gram-negative bacteria. LPS-induced excessive activation of toll-like receptor (TLR) 4 and subsequent cytokine storm is mainly implicated in the pathogenesis of septic shock and sepsis (Rathinam et al., 2019). The uncontrolled inflammatory cytokine storm during sepsis resulted in the dysregulation of the host response to infection, causing life-threatening multi-organ failure (Huang et al., 2019; Singer et al., 2016).

Macrophages, distributed throughout the body, are the first responders of the immune system and play an indispensable role in endotoxemia (Sheu and Hoffmann, 2022; Zhong et al., 2021). Macrophages are highly heterogeneous, and several macrophage subsets have different functions (Murray and Wynn, 2011). Classically activated macrophages (M1 macrophages), polarized by LPS alone or in combination with T helper 1 (Th1) cytokines, promote inflammatory cytokines production, leading to organ injury (Shapouri-Moghaddam et al., 2018). Alternatively activated macrophages (M2 macrophages), polarized by T helper 2 (Th2) cytokines, have anti-inflammatory and immunomodulatory effects (R. Wang et al., 2020). M1/M2 macrophage balance is critical for organ outcomes in inflammation and injury (Shapouri-Moghaddam et al., 2018).

Nuclear factor kappa B (NF-κB) is a family of transcription factors known to regulate the expression of inflammatory genes, playing an important role in inflammatory response (Kaltschmidt et al., 2021). The excessive activation of NF-κB contributed to the development of endotoxemia (Wang et al., 2019; Yu et al., 2007). AMP-dependent protein kinase (AMPK) is an evolutionarily conserved serine/threonine protein kinase, involved in the regulation of energy metabolism (Feng et al., 2022). Sirt1 is one of the members of the sirtuin family. As a NAD-dependent deacetylase, Sirt1 catalyzed the deacetylation of various protein substrates, such as forkhead box O (FOXO), the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1-α), p53, and NF-κB (Tinkov et al., 2021; Khan et al., 2018). Many studies showed that AMPK could activate silence information regulator transcript-1 (Sirt1), and AMPK/sirt1 signaling played a protective role in sepsis-induced multi-organ injury, including lung, heart, liver, and kidney (Li et al., 2019, Li et al., 2019; Yu et al., 2021; Sang et al., 2022). AMPK/Sirt1 signaling was reported to mediate Irisin's effect on pulmonary epithelial barrier dysfunction and down-regulate the expression of NF-κB, improving sepsis-induced acute lung injury (Li et al., 2019, Li et al., 2019). In addition, the activated AMPK/Sirt1 signaling protected against septic liver and kidney injury by enhancing autophagy (Yu et al., 2021; Li et al., 2019, Li et al., 2019). Therefore, the regulation of AMPK/Sirt1 signaling may provide a new therapeutic strategy for the treatment of sepsis and multi-organ injury.

Nicaraven ((±)-N, N' -(propylenedinicotinamide) dinicotinamide, AVS, Fig. 1A), a chemically synthesized hydroxyl radical scavenger, has been reported to have antioxidant and anti-inflammatory effects (Zingarelli et al., 2000; Yokota et al., 2000). AVS was found to attenuate ischemia-reperfusion injury in rats and reduce radiation-induced cellular or organ injury (Yokota et al., 2000; Kawakatsu et al., 2013). Our previous study also showed that AVS could inhibit endothelial activation and inflammation by inhibiting NF-κB pathway (Lin et al., 2021). This study was to investigate the effects of AVS on endotoxemia-induced systemic inflammation and organ injury, and the underlying mechanism of its action was also explored, with the aim to provide a new strategy for the treatment of endotoxemia.