Dual targeting of PI3Kδ and PPARα enhances antitumor activity via FoxO1 activation in follicular lymphoma

Abstract Although phosphoinositide 3-kinase-δ (PI3Kδ) inhibition demonstrates efficacy in relapsed/refractory follicular lymphoma (FL), its clinical benefit is often limited by adaptive resistance, underscoring the need for rational combination strategies. Here, we show that combining the PI3Kδ inhibitor linperlisib with the pan-peroxisome proliferator-activated receptor (PPAR) agonist chiglitazar, an agent that reprograms tumor metabolism, delivers robust antitumor activity across FL models, including cell-derived and patient-derived xenografts, with a favorable tolerability profile. The combined regimen promotes G1/S arrest and apoptosis, exerting complementary metabolic and signaling effects through glycolysis suppression, activation of PPARα-driven programs, and consequent reactivation of the transcription factor forkhead box protein O1 (FoxO1), which is repressed by PI3K/AKT signaling. Genetic depletion of FoxO1 attenuates treatment responses, identifying FoxO1 activity as both a pharmacodynamic biomarker and a potential predictor of therapeutic benefit. Compared with monotherapy, the combination consistently achieves superior tumor control in vivo without overt toxicity, supporting its clinical translation potential. Collectively, these data provide a mechanistic rationale for dual targeting of PI3Kδ and PPARα in FL and advocate for clinical evaluation of this combination with FoxO1 as a pharmacodynamic biomarker.