Hydrogen sulfide (H2S) is generated in mammalian tissues by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).Here, we investigate the role of H2S in adrenal insufficiency during endotoxemia.We found both CBS and CSE were expressed in murine adrenal gland.hn vivo, CSE expression was decreased in adrenal glands during endotoxemia.Not only lipopolysaccharide (LPS), but PAG (CSE inhibitor) and AOAA (CBS inhibitor) depressed plasma corticosterone response to adrenocorticotropic hormone (ACTH) in mouse.In primary cultured adrenocortical cells, LPS and PAG caused suppression in corticosterone production in response to ACTH.The slow-releasing H2S donor GYY4137 reversed the suppression of corticosterone production by LPS.Collectively, the present study establishes for the first time that LPS causes inhibition of H2S generation in adrenal glands, which further leads to the impaired corticosterone production.These data also demonstrates the therapeutic potential of H2S-releasing agents as a treatment for adrenal insufficiency in patients with sepsis.