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Therapeutic Activation of PPARα Inhibits Transformed Follicular Lymphoma Tumorigenesis via the FOXM1 Signaling Pathway

Year: 2025

Type: article

Abstract: Transformed follicular lymphoma (t-FL) is a subtype of follicular lymphoma (FL) characterized by aggressive behavior and poor treatment outcomes.Dysregulated glucose uptake and cell cycle disruption have been implicated in t-FL progression.Here, we found that PPARα is frequently low-expressed in transformed follicular lymphoma, and therapeutic activation of PPARα significantly represses the progression of t-FL in cell line-derived xenograft (CDX) and primary t-FL patient-derived xenograft (PDX) models in vivo.Mechanistically, activation of PPARα inhibits t-FL progression mainly through three different signaling pathways as follows: PPARα inhibits glycolysis in t-FL cells by blocking the HIF1α signaling pathway; activation of PPARα induces mitochondria-dependent apoptosis in t-FL cells by disrupting mitochondrial homeostasis; and PPARα transcriptionally inhibits FOXM1 expression, causing the downregulation of its downstream target genes and inducing cell cycle arrest in t-FL cells.Concurrently, knockdown of FOXM1 enhances the sensitivity of t-FL cells to chiglitazar, and overexpression of FOXM1 partially rescued the inhibitory effect of chiglitazar on t-FL cells, highlighting the involvement of the PPARα-FOXM1 axis in the antitumor effects of chiglitazar.These promising preclinical results support further clinical evaluation of chiglitazar as a potential therapeutic option for t-FL patients, providing a novel and effective treatment approach for this aggressive subtype of FL.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.116437