Nature Immunology, Published online: 15 June 2026; doi:10.1038/s41590-026-02568-6 Some patients with pyoderma gangrenosum harbor a mutation (R57C) in OTULIN that disrupts the interaction between OTULIN and LUBAC leading to hyperactivation in monocytes and enhanced susceptibility of keratinocytes to TNF-induced, caspase-dependent cell death. One patient treated with anti-TNF therapy showed clinical remission of skin ulceration.