Phoenixin-14 attenuates oxidative multi-organ damage in sepsis-induced rats

Sepsis is a critical clinical condition characterized by life-threatening multi-organ dysfunction resulting from a dysregulated host response to infection. This study evaluated the individual and combined anti-inflammatory effects of Phoenixin-14 (PNX-14) and vagus nerve stimulation (VNS), while exploring whether PNX interacts with nesfatin-1 signaling. Male Sprague-Dawley rats were assigned to six experimental groups, including sham-operated controls, and sepsis-induced groups with or without pretreatment with PNX-14 (50 µg/kg/day, i.p., 4 days) and/or transcutaneous auricular VNS (20 Hz, 30 min/day). Sepsis was induced using cecal ligation and puncture (CLP). At the 16th hour following CLP, tissue and serum samples were collected for assessment of proinflammatory cytokines (IL-6, TNF-α), oxidative stress markers (malondialdehyde, myeloperoxidase activity, glutathione, superoxide dismutase, catalase), histological changes, and immunohistochemical expression of PNX and nesfatin-1. Additionally, in vitro ileal contractility was evaluated. PNX-14 pretreatment attenuated sepsis-induced hypothermia and significantly reduced serum IL-6 and TNF-α levels. PNX-14 also reversed oxidative damage and restored antioxidant levels in the brain, heart, lung, and ileum. While VNS alone provided modest protection-primarily in cardiac and intestinal tissues-its combination with PNX-14 failed to produce additive effects and, in some instances, exacerbated oxidative damage. Histopathological findings supported the biochemical results, showing reduced tissue damage with PNX. Immunohistochemistry revealed that both PNX and VNS preserved PNX and nesfatin-1 expression. In vitro, reduced contractility of ileal strips due to sepsis induction was improved when the septic rats were pretreated with VNS. PNX-14 exerts potent protective effects against systemic inflammation and multi-organ oxidative stress in sepsis. Notably, VNS does not enhance PNX-14 efficacy and may interfere with its protective mechanisms. These findings highlight PNX-14 as a promising therapeutic candidate, while suggesting caution in combining it with neuromodulatory strategies.