A druggable copper-signalling pathway that drives inflammation

TLDR

Inflammation is a complex physiological response involving immune cells, whose excessive activation underlies many diseases, yet its molecular mechanisms remain incompletely understood. The study aims to demonstrate copper’s central role in regulating cell plasticity and to propose a therapeutic strategy that reprograms metabolism and epigenetic states. The authors identify reactive mitochondrial copper(II) that drives NAD(H) redox cycling in inflammatory macrophages and show that the copper‑targeting dimer LCC‑12 diminishes this pool, thereby shifting metabolism and epigenetics to counteract activation. They find that CD44 facilitates copper uptake, that copper‑dependent NAD+ maintenance promotes inflammatory programming, and that LCC‑12 disrupts this pathway, reducing inflammation in bacterial and viral mouse models.

Abstract

Abstract Inflammation is a complex physiological process triggered in response to harmful stimuli 1 . It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases 2–4 . The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper (ii) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD + enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper (ii) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.