A Metabolism-Driven Prognostic Model and PSMD14-SP1-GYS1 Axis Reveal Therapeutic Vulnerabilities in Melanoma

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Superior predictive accuracy across 4 cohorts (specific metrics not provided in abstract)

• Primary Outcome: Overall survival prediction using metabolism-related prognostic model (MRPM)

• Nnt Or Sensitivity: High-risk patients showed worse survival and immunotherapy response across melanoma and other cancers

• Confidence Interval: Not reported in abstract

Clinical Application

Requires genomic profiling capabilities and bioinformatics infrastructure for MRPM calculation Relevant to Australian melanoma management given high incidence rates. Would require validation in Australian populations and integration with existing PBS-funded genomic testing pathways Melanoma patients requiring prognostic stratification and immunotherapy response prediction

Abstract

Melanoma is a highly aggressive cutaneous malignancy characterized by a strong propensity for metastasis and therapy resistance, with its progression being closely linked to metabolic reprogramming. This study integrated multiomics data (The Cancer Genome Atlas, Gene Expression Omnibus, European Nucleotide Archive) and advanced machine learning to develop prognostic and immunotherapy prediction models for melanoma, focusing on 114 metabolism-related pathways. Cox regression identified 70 genes linked to survival, with functional enrichment revealing key metabolic pathway alterations. A metabolism-related prognostic model (MRPM) was constructed using 101 combinations of machine learning algorithms, demonstrating superior predictive accuracy across 4 cohorts. High-risk patients showed worse survival and immunotherapy response in melanoma and other cancers. Tumor microenvironment analysis revealed MRPM's negative correlation with immune infiltration and positive association with tumor purity. Single-cell sequencing highlighted MRPM gene enrichment in melanocytes. Mechanistically, GYS1 (the key gene in MRPM) emerged as a pivotal prognostic gene that promotes melanoma proliferation and metastasis. Regulatory studies uncovered SP1's transcriptional control of GYS1- and PSMD14-mediated stabilization of SP1 through K48-linked ubiquitination removal. In vivo validation confirmed that PSMD14 knockdown suppressed tumor growth through SP1-GYS1 axis disruption. This work establishes MRPM as a robust predictive tool and elucidates the PSMD14-SP1-GYS1 regulatory network as a potential therapeutic target in melanoma metabolism.

References

1. 1.Xie, J., Zhao, S., Wu, D., Ma, C., Yan, W., Zhang, P., Lu, Q., Wan, Z., Tang, Q., Li, L., Wang, M., & He, Y. (2026). A metabolism-driven prognostic model and PSMD14-SP1-GYS1 axis reveal therapeutic vulnerabilities in melanoma. Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2025.08.044