Senotherapeutic potential against xeroderma pigmentosum

Abstract

Xeroderma pigmentosum (XP) is an inherited photoaging syndrome caused by mutations in genes involved in the nucleotide excision repair (NER) pathway. XP patients exhibit hypersensitivity to ultraviolet (UV) radiation, leading to accelerated skin aging and requiring lifelong sun avoidance. Here, we demonstrate that UV-induced DNA damage triggers cellular senescence and up-regulates senescence-associated secretory phenotype (SASP) genes in melanocytes derived from an XP patient. To explore the potential therapeutics for XP, we developed a cisplatin-based drug screening system and identified JAK inhibitors and curcuminoids as promising senomorphic agents. In addition, two classes of senolytic agents, BCL-2-like protein inhibitors and HSP90 inhibitors, effectively eliminate senescent melanocytes. Further analysis demonstrates that senomorphic treatment effectively counteracts senescence and reduces SASP gene expression in XP-derived melanocytes. Moreover, genes in senescence-related pathways, including the JAK/STAT, Type I interferon (IFN-I), and PI3K/AKT pathways, which are activated by both UV irradiation and cisplatin treatment, are down-regulated by senomorphic treatment. This study highlights a potential senotherapeutic strategy for XP, which may help alleviate photoaging symptoms in XP patients.