EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes

• Published in: Toxicology (Amsterdam) 2024-11, Vol.511, p.154018, Article 154018
• Main Authors: Zhu, Huiling, She, Qiuyun, Li, Hongmei, Zhang, Ning, Huang, Weining, Xu, Yingping, Liu, Zhongrong, Liang, Yunsheng
• Format: Article
• Language: English
• Subjects: Acneiform rash; Caspase-3; EGFR-TKIs; GSDME; Pyroptosis; Xerosis
• ISSN: 0300-483X; 1879-3185; 1879-3185
• DOI: 10.1016/j.tox.2024.154018

Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.