Dual Targeting of PI3Kδ and PPARα Enhances Antitumor Activity via FoxO1 Activation in Follicular Lymphoma

Here, we demonstrate that the phosphoinositide 3-kinase-δ (PI3Kδ) inhibitor linperlisib combined with the pan-peroxisome proliferator-activated receptor (PPAR) agonist chiglitazar delivers robust antitumor activity across FL models, including cell-derived and patient-derived xenografts, with a favorable tolerability profile.

The combined regimen enforces G1/S arrest and apoptosis and exerts complementary metabolic–signaling effects by suppressing glycolysis, activating PPARα-driven programs, and relieving PI3K/AKT-mediated repression of forkhead box protein O1 (FoxO1). Genetic depletion of FoxO1 blunts treatment responses, indicating that FoxO1 activity is a pharmacodynamic biomarker and potential predictor of benefit. Compared with monotherapy, the combination consistently achieves superior tumor control in vivo without overt toxicity, indicating clinical translation potential.