Protoporphyrin IX Beyond Conventional Applications: A Review of Emerging Research Directions.

5-Aminolevulinic acid (5-ALA) is used clinically for photodynamic therapy and fluorescence-guided diagnosis and surgery due to its selective accumulation in malignant cells, where it is converted into photoactive protoporphyrin IX (PpIX) via the heme biosynthesis pathway. The resulting buildup allows for selective visualization or destruction of the tissue under specific light exposure, particularly in pre-malignant and malignant skin lesions, brain tumors, and bladder cancer. More recently, 5-ALA and 5-ALA-induced PpIX have attracted interest for emerging diagnostic and therapeutic approaches. For instance, PpIX is being investigated as a potential marker for liquid biopsy. PpIX-mediated photodynamic therapy also shows promise for targeting specific cancer cell populations, including dormant cancer cells and cancer stem cells. In addition, the benefits of 5-ALA in neurological and mental health are under investigation, as disruptions in heme biosynthesis are increasingly linked to neurodegenerative diseases, chronic fatigue, and mood and sleep disorders. This review highlights these expanding research directions, discusses current challenges, and explores potential opportunities for 5-ALA-based applications.