Gpr109a alleviates mammary fibrosis via PPARγ-mediated reduction of ROS and mitochondrial damage

Mammary fibrosis is a serious pathological process, which seriously threatens life and health. Gpr109a is a membrane receptor that has been reported to be protective in liver/lung fibrosis, but the mechanism of mammary tissue specificity still needs to be verified. Therefore, the purpose of this experiment was to explore the effect of Gpr109a on mammary fibrosis and its potential regulatory mechanism. The results show that Gpr109a deletion exacerbates the TGF-β induced mouse mammary fibrosis phenotype and mitochondrial damage (including mitochondrial nuclear shrinkage, cristae reduction, membrane potential decrease, and ATP reduction, etc.). However, backfilling of Gpr109a could effectively reverse the above experimental results. RNA-seq results of mice mammary gland tissue showed that Gpr109a knock-out significantly affect PPARγ signaling, which may be an important signal for alleviating fibrosis. Mechanistic results showed that silencing of PPARγ significantly blocked the alleviation effect of Gpr109a on mitochondrial damage and elevated fibrotic phenotype indicators in mMECs. However, activating PPARγ effectively reversed the above experimental phenomena. Further studies found that PPARγ alleviated mammary tissue fibrosis and mitochondrial damage by reducing ROS accumulation. In conclusion, Gpr109a/PPARγ signaling reduces the tendency of mammary fibrosis by reducing the accumulation of ROS and mitochondrial damage, suggesting that Gpr109a has the potential to become an anti-mammary fibrosis target.