Prohibitins PHB1/2 Orchestrate Mitochondrial Homeostasis, Oncogenic Signaling, and Therapeutic Resistance in Cancer

Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2) are highly conserved scaffold proteins forming heterodimeric complexes crucial for cellular physiology. While ubiquitously expressed and localized across mitochondria, nucleus, cytoplasm, and plasma membrane, their remarkable functional pleiotropy is profoundly exploited in cancer. Understanding how PHBs integrate into various oncogenic signaling networks and influence the tumor microenvironment is critical, especially given their emerging roles in therapeutic resistance to standard-of-care treatments like platinum drugs and PARP inhibitors. This review addresses the multifaceted roles of PHBs, bridging structural insights with their impact on cellular metabolism and immune responses.

This comprehensive review synthesizes the current understanding of Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2) in tumor biology, detailing their structural features, post-translational modifications, and integration into multiple oncogenic networks. Researchers systematically described how PHBs directly activate the RAS-RAF-MEK-ERK cascade and fine-tune the PI3K/Akt/mTOR axis through ubiquitination-dependent scaffolding and degradation of negative regulators. The analysis also dissected PHB's dual role in mitochondrial homeostasis, including cristae architecture, OMA1-OPA1 axis regulation, respiratory chain supercomplex assembly, metabolic substrate switching, and mitophagy. Furthermore, the review explored dynamic nucleocytoplasmic shuttling of PHBs, linking metabolic status to cell cycle progression, stemness, and epigenetic remodeling via transcription factor interactions. Finally, it summarized PHB expression patterns, prognostic value, and mechanisms of therapeutic resistance across various cancer types.

Prohibitin 1 (PHB1) directly activates the RAS-RAF-MEK-ERK cascade via regulated phosphorylation, while both PHB1 and PHB2 fine-tune the PI3K/Akt/mTOR axis through ubiquitination-dependent scaffolding and degradation of negative regulators. They also exert bidirectional control over Wnt/β-catenin and NF-κB pathways. A major focus revealed the dual role of the mitochondrial PHB complex: protecting cristae architecture and regulating the OMA1-OPA1 axis, orchestrating respiratory chain supercomplex assembly, metabolic substrate switching, and mitophagy. Simultaneously, PHBs suppress or, in specific contexts, promote reactive oxygen species signaling and ferroptosis. Dynamic nucleocytoplasmic shuttling of PHBs couples metabolic status to cell cycle progression, stemness, and epigenetic remodeling through interactions with transcription factors like E2F1, p53, and Sp1, and chromatin modifiers such as MLL2 and HDAC1. Within the tumor microenvironment, PHBs emerge as critical immunometabolic hubs, influencing macrophage polarization, cGAS-STING activation, and sexual dimorphism in immune responses. > The review provides an in-depth analysis of how PHBs confer resistance to platinum drugs, paclitaxel, PARP inhibitors, and radiotherapy, highlighting their significant role in therapeutic evasion.