The Lactate-lactylation circuitry in kidney fibrosis: cellular crosstalk from tubular metabolic reprogramming to macrophage effector functions.

Kidney fibrosis is the histopathological endpoint of chronic kidney disease, yet antifibrotic trials targeting individual molecular nodes have repeatedly failed to translate into patient benefit. The pattern suggests that renal fibrosis is sustained by a recurrent circuit rather than a linear cascade. Here we propose a tubular-macrophage lactate-lactylation circuit that integrates tubular and macrophage evidence into a single cellular axis. Injured tubular cells reprogramme glycolytically and generate a sustained lactate-rich niche. On both sides of the tubulointerstitial interface, lactate is converted into histone and non-histone lactyl-lysine (Kla) marks that lock in profibrotic transcription, derange mitochondrial function and dampen innate immune surveillance. Macrophage outputs, profibrotic macrophage programmes, innate-immune memory, paracrine activation of fibroblasts/pericytes and, in selected contexts, macrophage-to-myofibroblast transition, feed back on tubular cells and the stromal compartment through bidirectional vesicular and cytokine signalling, generating the recurrent topology that distinguishes a circuit from a linear pathway. The supporting evidence is uneven across compartments; we stratify each key claim by tier of evidence and map the circuit onto current biomarker and therapeutic strategies. The framework clarifies why single-node interventions have not succeeded, and points to combinations that engage substrate supply, lactylation machinery, transcriptional output and intercellular feedback in parallel.