Amir Modarresi Chahardehi, Esfandiar Mali, Arya Afrooghe, Amirmasoud Asadi, Amirreza Khalaji, Hamed Soleimani Samarkhazan, Hananeh Esmaeil Beygi, Amirhossein Mohagheghi, Maryam Khanbabaei, Heliya Haghani, Reza Arefnezhad, Fatemeh Rezaei‐Tazangi
The phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway and microRNA (miRNA) regulation have been implicated in the initiation and progression of acute leukemia. Despite significant progress in the understanding of leukemogenic mechanisms, current therapies remain limited by relapse, drug resistance, and poor long-term survival, underscoring the need for novel targeted strategies. This review provides the current evidence regarding the molecular interplay between PI3K/AKT/mTOR signaling and miRNA dysregulation in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We highlight key oncogenic and tumor-suppressive miRNAs, discuss their regulatory impact on critical genes (PIK3CA, AKT1, PTEN, and FMS-like tyrosine kinase 3 [FLT3]), and evaluate therapeutic approaches, including PI3K/AKT inhibitors and miRNA-based interventions. Furthermore, we identified existing controversies, methodological limitations, and unresolved research gaps. Finally, we emphasize the translational potential of miRNA-targeted therapies and pathway-specific inhibitors, providing insights into their integration into personalized treatment strategies for acute leukemia.