AKR1C3 is a cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids with broad substrate specificity 12. In androgen metabolism, AKR1C3 converts Δ4-androstenedione to testosterone in the classical pathway and reduces androsterone to 5α-androstane-3α,17β-diol in the alternative 'backdoor' pathway, both producing potent androgens 13. It also reduces estrone to 17β-estradiol and functions as a prostaglandin F2α synthase 12. Mechanistically, NADPH's abundance drives net reductase activity in vivo despite bidirectional in vitro potential 24. Clinically, AKR1C3 is significantly upregulated in multiple cancers with poor prognostic implications. In hepatocellular carcinoma, AKR1C3-dependent lipid droplet formation confers sorafenib resistance by regulating lipid and energy homeostasis 5, while an AKR1C3/NF-κB/STAT3 positive feedback loop drives proliferation and metastasis 6. In esophageal adenocarcinoma, AKR1C3 enhances radioresistance by inhibiting ferroptosis through HSPA5 stabilization 7. In castrate-resistant prostate cancer, AKR1C3-mediated testosterone production from weak androgen precursors maintains AR signaling 8, with dual AKR1C3/AR-variant inhibitors showing synergy with standard therapies 9. AKR1C3 inhibitors (indomethacin, medroxyprogesterone acetate) demonstrate therapeutic potential across these malignancies 610.