<p>Arsenic (As), a prevalent heavy metal, poses significant risks to the immune systems of living organisms. The spleen is considered one of the major immune organs of As-poisoned aquatic organisms. Zinc (Zn), known for its antioxidant and detoxification properties, may alleviate As-induced immune organ damage, but the underlying mechanism remains unclear. The P38 MAPK/Nrf2/HO- 1 signaling pathway is a crucial endogenous antioxidant pathway that protects organs and acts against cellular oxidative damage. This experiment was designed to investigate the splenic toxicity induced by As in carp and to evaluate the hypothesis that Zn alleviates oxidative stress and inflammatory injury induced by As via the P38 MAPK/Nrf2/HO- 1 signaling pathway. In the experiment, the spleen of the arsenic-exposed group exhibited significant endoplasmic reticulum dilation, formation of apoptotic bodies, and perinuclear cisternae, preliminarily confirming that As can cause severe tissue damage in the spleen of carp. Additionally, the transcriptional activity and protein synthesis of genes related to inflammatory response, oxidative stress, and apoptosis were significantly dysregulated. Notably, Zn supplementation significantly mitigated As-induced damage by enhancing antioxidant enzymes (CAT, SOD, GSH) and suppressing key mediators of stress and apoptosis (Nrf2, NF-κB, PERK, HSP60, and caspases). Additionally, Zn supplementation has been shown to mitigate As-induced spleen injury and associated pathological alterations, including inflammation and necrosis. These findings reveal, for the first time, that Zn alleviates As-induced spleen injury through the P38 MAPK/Nrf2/HO- 1 pathway, providing new insights into the detoxification mechanism of Zn and its potential application in mitigating heavy metal toxicity in aquaculture.</p> Graphical Abstract <p></p>