Nrf2/Bach1 axis regulates redox homeostasis and energy metabolism to optimize Sertoli cell-mediated efferocytosis

Abstract

Efferocytosis is energy-consuming, and continuous efferocytosis imposes metabolic burdens on the phagocytes. Sertoli cells (SCs) are specialized phagocytes in the testis for efferocytosis of non-viable germ cells and residual bodies. What remains elusive is how SCs integrate metabolic adaptations in response to efferocytosis. Here, we identify the Nrf2/Bach1 axis as an important molecular machinery of SC-mediated efferocytosis. Nrf2 activation during efferocytosis stabilizes Bach1 expression. Nrf2 activation or Bach1 overexpression promotes SC-mediated efferocytosis, while the opposite phenotype is incurred by Nrf2 inactivation or Bach1 deficiency, with oxidative stress being a contributing factor. Beyond experiencing attenuated glucose uptake and ATP production, Bach1-deficient SCs exhibit a reduced NAD⁺/NADH ratio, and restraining NAD⁺ consumption by inhibiting serine biosynthesis rescues their impaired efferocytosis. We further observe an up-regulation of anti-ferroptotic genes in SCs upon Bach1 deficiency and demonstrate a protective role of ferroptosis in this scenario. We thus propose that redox homeostasis and energy metabolism lie at the nexus of the Nrf2/Bach1 axis in the regulation of SC-mediated efferocytosis. Our study explores the regulatory role of the Nrf2/Bach1 axis in SC-mediated efferocytosis, which will lead to a better appreciation of SCs in male reproductive health.