Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.