STOML2 Maintains Pluripotency and Cell Cycle Integrity in Human Pluripotent Stem Cells via PHB–ERK Signaling

Human pluripotent stem cells (hPSCs) can self-renew indefinitely and differentiate into all three germ layers. However, the primary regulators of hPSC cell cycle dynamics remain unclear. To identify novel regulators of hPSC proliferation, transcriptomic profiling of undifferentiated hPSCs and somatic cells was performed via next-generation sequencing. Stomatin-like protein 2 (STOML2) and prohibitin (PHB) were among the upregulated genes in hPSCs and were closely associated with the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway. Temporal expression analysis indicated that STOML2 and PHB decreased during differentiation and increased during reprogramming. Short hairpin RNA (shRNA)-mediated knockdown of STOML2 in hPSCs caused phenotypic changes. Gene expression analyses demonstrated reduced OCT4, NANOG, PHB, and phosphorylated ERK, alongside increased differentiation markers across all three germ layers. The STOML2-PHB axis is essential for maintaining hPSC identity by sustaining ERK/MAPK activity and cell cycle structure. This study identified STOML2 as a key pluripotency regulator and provides new insight into intrinsic stem cell fate control.