PKP1 promotes lung cancer by modulating energy metabolism through stabilization of PFKP Ritoré Salazar, Félix Arenas, Alberto Matia González, Ana María Zaza, Alessandra Aagaard Thomsen, Emil Bruun Rovsing, Anne Giehm Mikkelsen, Jacob Noguera, Nelida Ines Medina Vico, Pedro Pablo Plakophilin-1 Phosphofructokinase TRIM21 Lung cancer is the leading cause of cancer-related deaths worldwide, with lung squamous cell carcinoma (LUSC) lacking effective targeted therapies. Recent studies have identified Plakophilin-1 (PKP1) as one of the most differentially overexpressed genes in LUSC. This is particularly intriguing given that PKP1 is primarily known as a desmosomal component involved in cell adhesion, typically regarded as a tumor suppressor. To elucidate its biological role, we performed a genome-wide CRISPR knockout screening in PKP1-deficient models, revealing a strong dependence on mitochondrial metabolism. Metabolic assays further demonstrated that PKP1 loss significantly disrupts both mitochondrial function and glycolytic activity. In contrast, cells expressing PKP1 display a metabolically hyperactive phenotype, characterized by elevated oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Building on these findings, we found that PKP1 depletion selectively reduces platelet-type phosphofructokinase (PFKP) levels, a key rate-limiting enzyme in glycolysis, by enhancing its ubiquitination and subsequent degradation. Functional rescue experiments confirmed that PFKP mediates the proliferative role of PKP1. These findings suggest that PKP1 overexpression in LUSC promotes a hyperactive metabolic state binding to TRIM21 and preventing PFKP degradation, facilitating tumor progression. These effects were consistently observed across multiple LUSC cell lines, underscoring the robustness of the mechanism. These findings highlight a potential therapeutic vulnerability in LUSC metabolic regulation. 2025-09-19T11:34:01Z 2025-09-19T11:34:01Z 2025-09-01 journal article Ritoré-Salazar, F., Arenas, A.M., Matia-González, A.M. et al. PKP1 promotes lung cancer by modulating energy metabolism through stabilization of PFKP. Biomark Res 13, 112 (2025). https://doi.org/10.1186/s40364-025-00815-w https://hdl.handle.net/10481/106487 10.1186/s40364-025-00815-w eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Springer