Fig. 4

Dysregulated lipid metabolism is involved in the pathogenesis of psoriasis (by Figdraw, www.figdraw.com). Adipokines secreted by hypertrophic adipocytes modulate skin inflammation. Additionally, circulating FFAs including SFAs and PUFAs play a critical role in the development of psoriasis. SFAs are able to induce Th1/Th17 differentiation by activating DCs and also stimulate myeloid DCs to produce various proinflammatory cytokines, such as IL-1β. These proinflammatory cytokines subsequently promote the secretion of chemokines and inflammatory cytokines from KCs, leading to the recruitment of neutrophils and monocytes to the skin. Moreover, SFAs modulate the NALP3 inflammasome in monocytes or macrophages and inflammasome-mediated IL-1β secretion through the activation of TLR2 and TLR4. The lipid peroxidation of KCs in psoriasis, which initiate with the accumulation of ROS, ultimately results in KC-ferroptosis. In brief, accumulated PUFAs are catalyzed to PUFA-CoA and finally esterified into PUFA-PLs, which undergo peroxidization to form PUFA-PL-OOH. PLOOH sensitizes the cell to ferroptosis by generating lipid hydroxyl radicals and lipid peroxyl radicals. Other than ferroptosis, excess saturated FFAs in nonadipose cells can elicit both ROS and ER stress through lipid metabolism and signaling pathways, ultimately leading to the cell death. FFAs support the survival of TRM cells in the epidermis as well. The bioactive LMs derived from n-3 PUFA and n-6 PUFA exhibit contrasting anti-inflammatory and pro-inflammatory properties in psoriasis, respectively. Specifically, specialized pro-resolving lipid mediators (SPMs) derived from n-3 PUFA, including LXs, RVs, PDs, and MaRs, may resolve the psoriatic inflammatory. Conversely, n-6 PUFA-derived LMs, such as PGE2 and LTB4, contribute to neutrophil chemotaxis and KC proliferation