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Here, we show that combining the PI3K\u03b4 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 PPAR\u03b1-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 PI3K\u03b4 and PPAR\u03b1 in FL and advocate for clinical evaluation of this combination with FoxO1 as a pharmacodynamic biomarker.<\/jats:p>","DOI":"10.1038\/s41419-026-08593-5","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T04:34:02Z","timestamp":1774240442000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual targeting of PI3K\u03b4 and PPAR\u03b1 enhances antitumor activity via FoxO1 activation in follicular lymphoma"],"prefix":"10.1038","volume":"17","author":[{"given":"Wenqin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangxiong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangru","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuman","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-5462","authenticated-orcid":false,"given":"Bing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9376-3450","authenticated-orcid":false,"given":"Jie","family":"Zha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"8593_CR1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.annonc.2020.11.008","volume":"32","author":"M Dreyling","year":"2021","unstructured":"Dreyling M, Ghielmini M, Rule S, Salles G, Ladetto M, Tonino SH, et al. 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