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

Follicular lymphoma (FL) frequently exhibits relapse and resistance to targeted therapy, underscoring the need for rational combinations. 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. Collectively, these data support the clinical evaluation of linperlisib plus chiglitazar in FL, with prospective assessment of FoxO1 activity as a pharmacodynamic biomarker.