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However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1\u03b2 reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the\n                    <jats:italic>SDHB<\/jats:italic>\n                    promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1\u03b2-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.7554\/elife.83064","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T06:15:11Z","timestamp":1689315311000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83064","source":"Crossref","is-referenced-by-count":27,"title":["Succinate mediates inflammation-induced adrenocortical dysfunction"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6150-9175","authenticated-orcid":true,"given":"Ivona","family":"Mateska","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042aqky30","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universit\u00e4t Dresden","place":["Dresden, 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