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Yet, most available therapies focus on downstream inflammatory and microbial manifestations, whereas upstream sebocyte dysregulation, which drives disease initiation, persistence and relapse, remains a less direct therapeutic target. This review synthesizes current evidence on the molecular regulation of sebocyte biology and examines therapeutic implications of a sebocyte\u2010centred disease model. Key regulatory pathways are discussed, including peroxisome proliferator\u2010activated receptor\u2010\u03b3 (PPAR\u03b3)\u2010dependent transcriptional control, the FoxO1\u2013mTORC1 nutrient\u2010sensing axis and GATA6\u2010mediated differentiation, alongside hormonal, genetic, microbial and environmental factors that influence sebocyte function. Single\u2010cell transcriptomic and spatial profiling studies are consistent with a proposed microdomain\u2010based model of the pilosebaceous unit that may help explain regional disease heterogeneity, variable therapeutic response and relapse. Established and emerging acne therapies are evaluated across four classical pathogenic domains: sebocyte dysregulation, follicular keratinization, microbial modulation and inflammation, showing that several non\u2010antibiotic strategies act across multiple pathogenic axes and may support antibiotic\u2010sparing approaches. Throughout, evidence is graded to separate established clinical evidence from translational, preclinical and hypothesis\u2010generating findings. The review links these mechanisms to practice, aligning with current guideline recommendations on limiting systemic antibiotic duration and on positioning hormonal therapy and newer topical agents. It aims to distinguish what is actionable now from sebocyte\u2010directed approaches that remain investigational and await phase III and comparative data. Because the sebocyte lies upstream of and integrates these domains, its modulation can, in principle, act across all four pathogenic pathways\u2014the rationale for pathway\u2010inclusive, sebocyte\u2010directed agents and current interest in PPAR\u03b3 modulation. Whether a single upstream agent can achieve the broad, durable disease control that now typically requires combination regimens remains to be established.<\/jats:p>","DOI":"10.1111\/jdv.70752","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:07:10Z","timestamp":1790770030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of sebocyte function in acne: A pathway\u2010inclusive review"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1646-2608","authenticated-orcid":false,"given":"Christos C.","family":"Zouboulis","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Immunology Universitaetsklinikum Ruppin\u2010Brandenburg, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg  Neuruppin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0908-5763","authenticated-orcid":false,"given":"Apostolos","family":"Pappas","sequence":"additional","affiliation":[{"name":"Food Science Graduate Program SEBS and the Rutgers Center for Lipid Research  New Brunswick New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2204-0583","authenticated-orcid":false,"given":"Katja","family":"Martin","sequence":"additional","affiliation":[{"name":"Medtextpert  Zwillikon Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4899-6639","authenticated-orcid":false,"given":"Mauro","family":"Picardo","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico Dell'immacolata \u2010 IDI\u2010IRCCS  Rome 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