Transmembrane proteins across cellular membranes: Emerging roles in non‑cancerous diseases (Review)

Transmembrane proteins (TMEMs) are encoded by genes sharing the ‘TMEM’ root symbol, historically assigned to genes predicted to encode membrane‑spanning proteins of unknown function. Although TMEMs have been studied extensively in cancer, their roles in non‑cancerous diseases have received comparatively less attention. The present review summarizes the experimentally supported subcellular localizations of TMEMs and organizes their associations with non‑cancerous diseases according to shared biological mechanisms, including ion channel and phospholipid scrambling activity, store‑operated Ca²⁺ entry, lysosomal and autophagic function, mitochondrial homeostasis, endoplasmic reticulum function and membrane trafficking, immune sensing, mechanotransduction, cytoskeletal regulation and signal transduction. The type and strength of evidence supporting each association are indicated, distinguishing human causal variants from genetic susceptibility, experimental and expression data. This framework reveals that apparently unrelated diseases can arise from disruption of the same cellular process, that a single TMEM, such as TMEM16A, can act through different mechanisms in different tissues, and that homologous paralogs may diverge in function. Strong human causal evidence remains restricted to a few TMEMs, such as TMEM16F, ORAI1, TMEM240 and TMEM126B. Translational feasibility, current knowledge gaps and future directions for developing TMEMs as therapeutic targets and biomarkers are also discussed.