Dietary limonin ameliorates heart failure with preserved ejection fraction by targeting ferroptosis via modulation of the Nrf2/SLC7A11/GPX4 axis: an integrated transcriptomics and metabolomics analysis

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Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by hypertension, metabolic disorders, and impaired diastolic function, with limited therapeutic options. Recent studies have highlighted the role of ferroptosis in the pathogenesis of HFpEF, and the inhibition of ferroptosis occurrence can significantly improve cardiac function. Limonin, a bioactive ingredient derived from citrus fruits, has been confirmed to exert potential anti-inflammatory and antioxidant effects in some cardiovascular diseases. This study aims to investigate the therapeutic effects of limonin on HFpEF and the underlying mechanisms of inhibiting ferroptosis. HFpEF mice were established by a combination of Nω-nitro-L-arginine methyl ester and a high-fat diet for 6 weeks. Subsequently, the HFpEF mice were treated with empagliflozin or limonin via oral gavage for an additional 6 weeks. Limonin curbed body weight gain and improved metabolic disorders and hypertension. Limonin also ameliorated concentric cardiac hypertrophy and diastolic dysfunction. Transcriptomics and metabolomics analyses revealed that limonin regulated ferroptosis-related pathways and lipid peroxidation. In vivo, limonin improved mitochondrial morphology, reduced cardiac Fe2+ levels and ferroptosis markers such as ROS, 4-HNE and MDA, and increased GSH levels, thereby enhancing antioxidant capacity. Mechanistically, limonin regulated the P53/SLC7A11/GPX4 signaling pathway, promoted the nuclear translocation of Nrf2 (its upstream signaling molecule), and subsequently activated its downstream antioxidant elements, ultimately inhibiting ferroptosis. Furthermore, limonin decreased the expressions of ACSL4, COX2, and ALOXs, which reduced the accumulation of lipid peroxides. These results demonstrate that limonin ameliorates HFpEF by targeting ferroptosis via modulation of the Nrf2/SLC7A11/GPX4 axis, providing a novel strategy for HFpEF treatment.

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