热凋亡是一种炎症性程序化细胞死亡(PGD)，据报道与N6-甲基腺苷（m6A）修饰有关。本研究旨在调查m6A去甲基化酶AlkB同源物5（ALKBH5）在慢性光化性皮炎(CAD)进程中热凋亡的机制。运用定量逆转录聚合酶链反应（qRT-PCR）评估CAD和正常样本之间的m6A相关基因变化。将人角质形成细胞（HaCaT细胞）暴露于紫外线B（UVB；10,20和30 mJ/cm2），随后评估细胞增殖、细胞凋亡、炎症细胞因子（白介素(IL)-1β、IL-18和肿瘤坏死因子(TNF-α)）、热凋亡相关蛋白（气孔美凋亡蛋白(GSDMD)，半胱氨酸酶-1(Caspase-1)和半胱氨酸酶-4(Caspase-4)）。将靶向ALKBH5的小干扰RNA(siRNA)转染入HaCaT细胞，评估si-ALKBH5对CAD的影响。通过暴露紫外线B（每天250 mJ/cm2）诱导CAD小鼠模型，以确认ALKBH5在CAD中的作用。CAD患者中ALKBH5表达增加。紫外线B也促进了ALKBH5的表达，增加了细胞凋亡，并诱导了炎症因子（IL-1β、IL-18和TNF-α）的释放以及热凋亡相关蛋白（GSDMD，Caspase-1和Caspase-4）。沉默ALKBH5抑制了细胞凋亡，并抑制了紫外线B诱导的热凋亡和炎症反应。同时，沉默ALKBH5减轻了CAD小鼠紫外线B诱导的皮肤损伤，伴随炎症细胞因子和热凋亡相关蛋白表达的减少。本研究有助于进一步了解ALKBH5在CAD诱导的热凋亡中的作用机制，并为CAD的研究与管理提供了新的思路。© 2023. 作者(们)独家授权给施普林格科技传媒有限责任公司，施普林格自然出版集团的一部分。

Pyroptosis is an inflammatory programmed cell death (PCD) and is reported to be associated with N6-methyladenosine (m6A) modification. This study aimed to investigate the mechanism of m6A demethylase AlkB homolog 5 (ALKBH5) in pyroptosis in the process of chronic actinic dermatitis (CAD). Changes of m6A-related genes were evaluated between CAD and normal samples using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Human keratinocytes (HaCaT cells) exposed to ultraviolet B (UVB; 10, 20, and 30 mJ/cm2), followed by evaluation of cell proliferation, cell apoptosis, inflammatory cytokines (interleukin (IL)-1β, IL-18, and tumor necrosis factor (TNF-α)), and pyroptosis-related proteins (gasdermin D (GSDMD), Caspase-1, and Caspase-4). Small interfering RNA (siRNA) targeting ALKBH5 was transfected into HaCaT cells to assess the effect of si-ALKBH5 on CAD. A CAD mice model was induced after exposure to UVB (250 mJ/cm2 per day) to confirm the role of ALKBH5 in CAD. AKKBH5 was highly expressed in CAD patients. UVB also promoted ALKBH5 expression, increased cell apoptosis, and induced the release of inflammatory cytokines (IL-1β, IL-18, and TNF-α) as well as pyroptosis-related proteins (GSDMD, Caspase-1, and Caspase-4). Silencing ALKBH5 repressed cell apoptosis and suppressed UVB-induced pyroptosis and inflammatory response. Meanwhile, silencing ALKBH5 attenuated UVB-induced skin damage of CAD mice, accompanied with the reduction in expression of inflammatory cytokines and pyroptosis-related proteins. This study helps to further understand the mechanism of ALKBH5 in CAD-induced pyroptosis and provides novel ideas for the research and management of CAD.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.