Lactate/AARS1/H3K18la/LDHA positive feedback loop triggers ferroptosis, which participates in diabetic nephropathy via the modulation of ACSL4 transcription

Diabetic nephropathy (DN) is one of the most severe complications associated with diabetes. Recent studies have demonstrated that lactate-mediated histone lactylation is involved in diabetes-related complications. Moreover, alanyl-tRNA synthetase 1 (AARS1) has been identified as a novel lactyltransferase capable of modulating histone H3 lysine 18 lactylation (H3K18la). In this study, we aim to determine whether and how AARS1-mediated H3K18la participates in the pathogenesis of DN. Our data indicate that the levels of lactate, lactate dehydrogenase A (LDHA), lactylation and H3K18la are increased in DN patients and models. Moreover, decreasing lactate levels through oxamate attenuates lactylation and H3K18la, improves renal function, and decreases cell death in DN models. Furthermore, lactate-mediated H3K18la promotes ferroptosis via the modulation of acyl-CoA synthetase long-chain 4 (ACSL4) transcription. AARS1 is subsequently shown to be increased in DN models. In addition, AARS1 lactylates H3K18 to modulate ACSL4 transcription in DN. Furthermore, lactate, LDHA and AARS1 regulate each other through H3K18la, thus forming a positive feedback loop. Importantly, inhibiting AARS1-induced lactylation via β-alanine has been shown to interrupt the lactate/AARS1/H3K18la/LDHA positive feedback loop, thus inhibiting ferroptosis in DN models. In conclusion, β-alanine may represent an effective therapeutic strategy for DN by disrupting the lactate/AARS1/H3K18la/LDHA positive feedback loop.