The p38 mitogen-activated protein kinase (p38-MAPK) is a crucial signaling pathway closely involved in several physiological and cellular functions, including cell cycle, apoptosis, gene expression, and responses to stress stimuli. It also plays a central role in inflammation and immunity. Owing to disparate p38-MAPK functions, it has thus far formed an elusive drug target with failed clinical trials in inflammatory diseases due to challenges including hepatotoxicity, cardiac toxicity, lack of efficacy, and tachyphylaxis, which is a brief initial improvement with rapid disease rebound. To overcome these limitations, downstream antagonism of the p38 pathway with a MAPK-activated protein kinase (MAPKAPK, also known as MK2) blockade has demonstrated the potential to abrogate inflammation without the prior recognized toxicities. Such MK2 inhibition (MK2i) is associated with robust suppression of key pro-inflammatory cytokines, including TNFα and IL-6 and others in experimental systems and in vitro. Considering this recent evidence regarding MK2i in inflammatory arthritis, we revisit the p38-MAPK pathway and discuss the literature encompassing the challenges of p38 inhibitors with a focus on this pathway. We then highlight how novel MK2i strategies, although encouraging in the pre-clinical arena, may either show evidence for efficacy or the lack of efficacy in emergent human trials data from different disease settings.

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.−57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.−57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.−57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.

Mutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence. Population-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4. The prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations. There is a low probability (<2%) of detecting a germline CDKN2A mutation in people with melanoma except for those with a strong family history of melanoma (≥2 affected relatives, 25%), three or more primary melanomas (29%), or more than one primary melanoma who also have other affected relatives (27%).

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher’s exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Ultraviolet (UV) radiation induces DNA damage and oxidative stress in melanocytes, shaping pigmentation phenotypes and elevating photocarcinogenesis risk. Human models that capture donor-specific genetic determinants of UV sensitivity remain limited. Here, we establish a genotype-driven UV response model using induced pluripotent stem cell (iPSC)-derived melanocytes from donors carrying defined MC1R variants. Differentiated cells recapitulated melanocytic morphology, marker expression, and pigmentation consistent with donor sun-sensitivity traits. Following narrowband UVB exposure, UV-sensitive lines exhibited reduced survival, prolonged checkpoint activation, and delayed cyclobutane pyrimidine dimer (CPD) repair. Mechanistic analysis revealed that the interferon-regulated GTPase MX2 amplifies UV-induced p53 and p38 activation while promoting apoptosis independently of AKT. These findings identify MX2 as a physiological enhancer of DNA damage signaling in normal melanocytes, distinct from its interferon-mediated role in melanoma. Our study provides a human-relevant platform linking pigmentation genotype to UV resilience and supports iPSC-derived systems as New Approach Methodologies (NAMs) for mechanistic and translational phototoxicology.