biostudies-literatureGomes KPUniveristy Hospital Foundation2384-2408https://www.ebi.ac.uk/biostudies/studies/S-EPMC12423331biostudies-literatureUnknown17(9)Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated fatty acids (SFAs) have been linked to lipotoxicity. In this study, patients with secondary lymphedema showed a significantly lower plasma polyunsaturated to saturated fatty acid (PUFA/SFA) ratio compared to BMI-matched controls. Stearic acid, a common dietary SFA, induced apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in human lymphatic endothelial cells. In a mouse model, a short-term high-SFA diet was used to lower the plasma PUFA/SFA ratio, which worsened tail swelling, oxidative stress, ER stress, and tissue damage following lymphatic injury. Switching to a standard chow diet after surgery prevented these effects. Patients with lymphedema also exhibited elevated levels of fatty acid-binding protein 4 (FABP4), a lipid chaperone associated with metabolic stress. FABP4 inhibition reduced stearic acid-induced cell death in vitro and mitigated tissue damage in vivo. These findings suggest a pathogenic role for SFAs and support dietary modulation and FABP4 inhibition as potential therapeutic strategies for lymphedema.EMBO molecular medicineSaturated fatty acids induce lipotoxicity in lymphatic endothelial cells contributing to secondary lymphedema development.PMC12423331RES0056514Yang XMunhoz JPatel NGoruk SField CJGomes KPGibson SBKorodimas JLiu EfalseSaturated fatty acids induce lipotoxicity in lymphatic endothelial cells contributing to secondary lymphedema development.Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated fatty acids (SFAs) have been linked to lipotoxicity. In this study, patients with secondary lymphedema showed a significantly lower plasma polyunsaturated to saturated fatty acid (PUFA/SFA) ratio compared to BMI-matched controls. Stearic acid, a common dietary SFA, induced apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in human lymphatic endothelial cells. In a mouse model, a short-term high-SFA diet was used to lower the plasma PUFA/SFA ratio, which worsened tail swelling, oxidative stress, ER stress, and tissue damage following lymphatic injury. Switching to a standard chow diet after surgery prevented these effects. Patients with lymphedema also exhibited elevated levels of fatty acid-binding protein 4 (FABP4), a lipid chaperone associated with metabolic stress. FABP4 inhibition reduced stearic acid-induced cell death in vitro and mitigated tissue damage in vivo. These findings suggest a pathogenic role for SFAs and support dietary modulation and FABP4 inhibition as potential therapeutic strategies for lymphedema.2025-01-01T00:00:00Z2025 Sep2026-06-03T02:27:51.595Z2026-04-23T03:10:30.942ZS-EPMC124233314075979410.1038/s44321-025-00286-4