Deep subsurface microorganisms play crucial roles in global element cycling, but their adaptation to hydrostatic pressure changes remains unclear. This study investigated the piezotolerant iron reducer Orenia metallireducens Z6 (strain Z6) under a gradient of high hydrostatic pressures (HHP) (0.1, 10, 20, 30 and 40 MPa). Supplied with glucose and ferrihydrite (Fe₂O₃·0.5H₂O), strain Z6 maintained stable iron-reducing activity at 0.1-30 MPa but was significantly inhibited at 40 MPa. The optimum protein concentration was observed at 20 MPa (138.62 µg/mL) compared to those (102.15-119.72 µg/mL) at other pressures. In addition, decreased ethanol yield, but elevated CO₂ production and Fe(II)/glucose ratio (R_{Fe(II):glucose}) occurred at the inhibitive 40 MPa, under which ferrihydrite acted as an electron sink to facilitate favorable thermodynamics and biosynthesis. Transcriptomics revealed the universal stress responses (e.g., antioxidant defense systems, DNA/protein repairment, ion transport, compatible solute formation, membrane lipid composition, and EPS-formation), while specific metabolic pathways were pressure-dependent. Compared to the genes associated with antitoxin, cell motility, competence, stress responses were overexpressed under 10-30 MPa, some genes related to phosphotransferase system (PTS) and cold shock responses were only upregulated at 40 MPa. The findings provide novel insights about the adaptive evolution of piezotolerant/piezophilic organisms. The significance of oxidized iron minerals and their contribution to element cycling in deep subsurface environments is also underscored.