Comparative Interactome Analysis Reveals Architectural Principles Governing K⁺ Channel Function in Cancer

Potassium (K⁺) channels have been frequently linked to cancer progression; however, their contribution varies across tumour types and experimental models. This heterogeneity indicates that gene-level characteristics such as expression, co-expression, or mutational status are inadequate for explaining channel involvement in oncogenic signalling. Here, we performed a cross-study comparison of experimentally validated K⁺ channel interactomes, we show that K⁺ channel regulation is highly context-dependent and does not exhibit conserved pan-cancer signatures. By directly comparing proximity-labeling and affinity-purification datasets across different K⁺ channel families, we identify a limited number of recurrent organizational architectures rather than universal signalling modules. KCa3.1 (encoded by KCNN4), Kir2.1 (KCNJ2), and TASK-1 (KCNK3) assemble signalling-permissive interactomes integrating adhesion complexes, junctional scaffolds, vesicular trafficking pathways, and receptor-associated signalling nodes. In contrast, Kv11.1 (encoded by KCNH2) displays an interactome predominantly enriched for proteostasis and endoplasmic reticulum-associated components, indicating a proteostasis-centered organizational profile with comparatively limited signalling integration. Kv1.3 (encoded by KCNA3), instead, consistently associates with mitochondrial and metabolism-linked proteins and functionally connects metabolic state to downstream transcriptional regulators, rather than regulating its own transcription. Higher-order intersection and pathway-specific analyses indicate that functional convergence across the above channels emerges from shared architectural principles rather than extensive molecular overlap. In conclusion, this study identifies interactome architecture as a central organizational level for understanding K⁺ channel function in cancer. The integration of pan-cancer gene-level analyses with systematic comparison of interaction architectures offers a coherent framework for interpreting the functional heterogeneity observed across channels, families, and tumor contexts. This perspective suggests that therapeutic strategies may benefit from targeting channel-centered network architectures rather than isolated channels alone, highlighting ion channels as structural components of broader signalling systems rather than solely bioelectrical regulators.