Phosphodiesterase 4 (PDE4) enzymes play a central role in modulating cyclic adenosine monophosphate (cAMP) signaling and regulating diverse cellular responses. Inhibitors of PDE4 have emerged as safe and effective anti-inflammatory therapies across multiple dermatologic diseases, and growing evidence suggests that PDE4 inhibition exerts broader effects on skin physiology. This review synthesizes mechanistic, preclinical, and clinical evidence describing the multifaceted roles of PDE4 inhibition in the skin. A comprehensive literature review was conducted using PubMed/MEDLINE, Embase, and ClinicalTrials.gov through 2025. Search terms included "PDE4," "phosphodiesterase 4," and both approved and investigational therapies, including "apremilast," "crisaborole," "roflumilast," and "orismilast." Relevant preclinical studies, clinical trials, and mechanistic investigations were included. PDE4 inhibition prevents cAMP degradation and activates protein kinase A (PKA) signaling, leading to broad biologic effects in the skin. Beyond well-established anti-inflammatory actions, PDE4 inhibitors appear to influence melanocyte signaling and pigmentation, enhance epidermal barrier protein expression, modulate sensory neuron activity, and promote wound healing by reducing fibrosis. These effects have been demonstrated mechanistically and across multiple dermatologic conditions and may help explain clinical observations. Heterogeneity in study design, limited long-term data, and variability in PDE4 isoform selectivity across studies may limit generalizability. Further mechanistic and comparative clinical studies are needed to better define therapeutic impact. PDE4 inhibitors represent a unique therapeutic class with pleiotropic effects across multiple disease states, including regulation of pigmentation, barrier integrity, neural signaling, and tissue repair. Their ability to integrate immunologic and non-immunologic pathways highlights their role in maintaining cutaneous homeostasis and expanding therapeutic potential in dermatology.
Khodadad et al. (Sun,) studied this question.