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The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV , encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans. [Display omitted] • A chemical screen identifies sex hormone catabolites as specific pyrin activator • The pyrin activation mechanism is human specific and B30.2 dependent • Patients with specific mutations in pyrin are highly responsive to the catabolites • This sterile inflammatory activity likely explains the experimental steroid fever Magnotti et al. use a chemical screen to identify pyrin inflammasome activators acting primarily on pyrin step 2. Pregnanolone and etiocholanolone, two catabolites of progesterone and testosterone, activate human pyrin in a B30.2-dependent manner. Pyrin-mutated PAAND patients are highly responsive to pregnanolone. These endogenous catabolites could contribute to sterile (auto)inflammation. [ABSTRACT FROM AUTHOR]