Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions.

The cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.