2. Academic Validation
  3. 4-Octyl itaconate inhibits inflammation to attenuate psoriasis as an agonist of oxeiptosis

4-Octyl itaconate inhibits inflammation to attenuate psoriasis as an agonist of oxeiptosis

  • Int Immunopharmacol. 2023 Sep 21;124(Pt B):110915. doi: 10.1016/j.intimp.2023.110915.
Mengshu You 1,  Qian Jiang 1,  Huining Huang 2,  Fangyu Ma 3,  Xingchen Zhou 4
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 2 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 3 Department of Health Management Center, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. Electronic address: waterxiaoyu@126.com.
  • 4 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: zhouxingchen117@163.com.
PMID: 37741130 DOI: 10.1016/j.intimp.2023.110915
Abstract

Psoriasis is a highly prevalent chronic disease associated with a substantial social and economic burden. Oxeiptosis is a programmed cell death that occurs when cells are in a state of high oxidative stress, which has a potent anti-inflammatory effect. However, there is still no research on oxeiptosis in psoriasis, and the agonists or antagonists of oxeiptosis remain an unclear field. Here, we found that oxeiptosis of keratinocytes was inhibited in psoriasis lesions. KEAP1, as the upstream molecular component of oxeiptosis, is highly expressed in psoriasis lesions. Knockdown of KEAP1 in HaCaT cells caused oxeiptosis in the condition of M5 cocktail stimulation. Next, we found that the cell-permeable derivative of itaconate, 4-octylitaconate (OI) promoted oxeiptosis of keratinocytes by inhibiting KEAP1 and then activating PGAM5 which are two upstream molecular components of oxeiptosis. At the same time, OI can reduce the expression of inflammatory cytokines induced by M5 cocktail stimulation in vitro. Similarly, we found that OI can alleviate IMQ-induced psoriatic lesions in mice and downregulate the levels of inflammatory cytokines in psoriatic lesions. In summary, our findings suggest that oxeiptosis of keratinocytes was inhibited in psoriasis and OI can significantly inhibit inflammation and alleviate psoriasis as an agonist of oxeiptosis, indicating that oxeiptosis may be involved in regulating the progression of psoriasis, which may provide new therapeutic targets for psoriasis treatment.

Keywords

4-octyl itaconate; AIFM1; KEAP1; Oxeiptosis; Psoriasis; ROS.

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