PTTG3P-miR-142-5p-IGF2BP3 axis governs ferroptosis in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is resistant to therapy and carries high mortality. Ferroptosis is a promising therapeutic target in which long non-coding RNAs may be involved. This study aimed to investigate the regulatory role of the PTTG3P-miR-142-5p-IGF2BP3 axis in ferroptosis during HCC, revealing the potential mechanisms by which this axis influences HCC initiation and progression. Methods Bioinformatics analysis revealed the expression and prognostic significance of PTTG3P in HCC. Concurrently, overexpression and knockdown models of PTTG3P, miR-142-5p, and IGF2BP3 were established to detect intracellular levels of ferroptosis regulatory factors. Gene interactions were explored via western blot, quantitative real-time PCR, and luciferase reporter assays. Finally, in vivo experiments validated the role of the PTTG3P-miR-142-5p-IGF2BP3 axis in tumorigenesis. Results PTTG3P was upregulated in HCC and associated with poor prognosis. PTTG3P was a molecular sponge for miR-142-5p, leading to IGF2BP3 derepression and modulation of ferroptosis proteins, NRF2, SLC7A11 and GPX4. PTTG3P overexpression in HepG2 cells increased ferroptosis resistance, while PTTG3P knockdown in Huh7 cells sensitized these cells to ferroptosis. Additionally, the PTTG3P/miR-142-5p/IGF2BP3 axis influenced tumor growth in a xenograft mouse model. Conclusion The PTTG3P/miR-142-5p/IGF2BP3 axis is a master regulator of ferroptosis in HCC. PTTG3P is a competing endogenous RNA (ceRNA) which sustains IGF2BP3-mediated ferroptosis resistance. Targeting the axis sensitizes HCC to ferroptosis and is potentially a novel therapeutic target to combat treatment resistance.