The PI3K/AKT/mTOR signaling pathway plays a central role in regulating cell growth, proliferation,
metabolism, and survival. Dysregulation of this pathway is frequently observed in cancer and
metabolic disorders. In recent years, microRNAs (miRNAs) — small non-coding RNAs of about 22
nucleotides — have emerged as critical modulators of this cascade, acting either as oncogenic
drivers or tumor suppressors. Several miRNAs function as oncomiRs, promoting PI3K/AKT/mTOR
activation. For instance, miR-21, one of the most studied, targets PTEN, a key negative regulator of
PI3K, leading to AKT hyperactivation and enhanced tumor growth. Similarly, miR-221/222 inhibit
PTEN and p27^Kip1, stimulating cell proliferation and resistance to apoptosis. Conversely, miR-126,
miR-145, and miR-99a act as tumor suppressor miRNAs. MiR-126 downregulates p85β, a regulatory
subunit of PI3K, thereby limiting AKT activation. MiR-99a and miR-100 directly target mTOR,
reducing protein synthesis, angiogenesis, and tumor progression. Altered expression of these
miRNAs has been linked to cancers of the breast, lung, prostate, and colon, as well as to insulin
resistance. Clinically, expression profiles of miRNAs regulating the PI3K/AKT/mTOR pathway are
being explored as biomarkers for prognosis and therapeutic response, particularly to PI3K or mTOR
inhibitors. Ongoing research suggests that combined strategies — targeted drugs together with
miRNA modulation — may enhance treatment efficacy in tumors driven by aberrant PI3K/AKT/mTOR
signaling.