Microproteins, once overlooked due to their small size and non-canonical origins, have been recently identified as essential regulators of diverse biological processes, including mitochondrial function, cell signaling, and immune responses. Their study has been propelled by recent technological advances in identifying and characterizing microproteins, revealing their significant role in health and disease. This review comprehensively summarizes these advances and recent insights into the epigenetic, transcriptional, translational, and proteostatic regulation of microproteins and their regulatory effects on oncogenic targets such as KRAS and EGFR. We emphasize clinical and translational opportunities, including using microproteins as therapeutic targets and as templates for modality design (e.g., stabilized therapeutic peptides and molecular glues), alongside their value as biomarkers and potential companion diagnostics. Finally, we outline key challenges that must be addressed to enable therapeutic development, especially in microprotein detection, structure and interaction analysis, context-specific expression prediction, and functional characterization in vivo. Addressing these gaps will help convert microprotein biology more effectively into translational medicine.

Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSis) often have limited efficacy in patients with advanced prostate cancer (PCa) (especially AR-negative). Inducing ferroptosis in PCa cells is an attractive therapeutic approach. In this work, mesoporous polydopamine nanoparticles (MPDA NPs) were developed to simultaneously deliver Cu⁺/Cu²⁺ ion pairs and glutathione peroxidase 4 (GPX4) inhibitor RSL3 to tumor sites for enhanced treatment of PCa. The prepared MPDA-Cu-RSL3@HA (MPCRH) NPs induced ferroptosis by promoting lipid peroxidation and regulating phospholipid profiles in PCa cells, and the above effects were further enhanced by mild photothermal therapy (mPTT) without damaging normal tissues. mPTT can promote reactive oxygen species (ROS) generation and degrade tumor extracellular matrix in vivo to promote nanodrugs intratumoral penetration. In short, this work shows the great application potential of mPTT-enhanced nano-ferroptosis inducers in the field of PCa treatment, in order to provide a reasonable paradigm for nanodrug development and PCa treatment.