FABP5 reprograms lipid metabolism and promotes cutaneous T-cell lymphoma progression via activation of PPARγ signalling

Background Cutaneous T-cell lymphoma (CTCL) constitutes a rare and heterogeneous group of T-cell lymphomas with an unclear pathogenesis. There is emerging evidence that fatty acid binding protein 5 (FABP5) regulates the PPARγ signalling pathway through its binding to fatty acids. However, the precise biological role of FABP5 in CTCL remains unclear. Aim To investigate the expression of FABP5 in CTCL and evaluate the effects of targeting FABP5 on the biological behaviors of CTCL tumour cells. Methods We performed single-cell transcriptomic analysis to evaluate the expression of FABP5, fatty acid synthase (FASN), and cholesterol regulatory element binding protein (SREBP1) in CTCL patients. FABP5 was knocked down using short interfering RNA (siRNA) lentiviruses, and mRNA expression of FABP5 in CTCL cell lines was quantified by real-time quantitative reverse transcription PCR (RT-qPCR). Cell proliferation and invasion were assessed using CCK-8 and transwell assays, while apoptosis and cell cycle distribution were analysed by flow cytometry. The impact of FABP5 on epithelial-mesenchymal transition (EMT) was investigated via qRT-PCR and Western blot. Intracellular levels of free fatty acids (FFAs), total cholesterol (TC), and triglycerides (TG) were measured with assay kits. The effect of BMS-309403 (a competitive inhibitor of FABP5) on the biological behavior of CTCL cells was also studied. Results FABP5 expression was significantly elevated in CTCL patients and cells compared to healthy controls, and silencing FABP5 inhibited cell proliferation. FABP5 knockout upregulated E-cadherin and downregulated N-cadherin and vascular endothelial growth factor (VEGF), thereby inhibiting EMT. Intracellular levels of FFAs, TC, and TG were also reduced. Bristol-Myers Squibb-309403 (BMS-309403) decreased cell viability, induced apoptosis, and lowered TC, TG, and peroxisome proliferator-activated receptor-γ (PPARγ) levels. Limitations The study relied solely on in vitro experiments using cell lines. Animal models would strengthen the translational relevance of the findings. In addition, the precise molecular interactions between FABP5 and PPARγ signalling in CTCL remain unclear. Conclusion Our findings suggest that the FABP5/PPARγ axis is a promising therapeutic target in CTCL, with BMS-309403 emerging as a potential agent to reverse lipid metabolic reprogramming in CTCL.