Background <p>Diabetic Kidney Disease (DKD) is a major complication driven by chronic inflammation and impaired tissue homeostasis. While mesenchymal stem cells (MSCs) show promise, the precise mechanisms by which human adipose-derived MSCs (hASCs) modulate macrophage-mediated resolution of inflammation remain to be fully elucidated.</p> Methods <p>We integrated single-cell RNA sequencing (scRNA-seq) analysis of human DKD kidneys with in vivo evaluations in db/db mice and in vitro co-culture models. We employed transcriptomic and molecular approaches to systematically investigate how hASCs impact macrophage functional states.</p> Results <p>scRNA-seq revealed a significant dysregulation of phagocytosis and efferocytosis pathways in human DKD macrophages. In vivo, hASCs effectively homed to injured kidneys, improved renal filtration, and attenuated pathological injury. Rather than a simple binary pro-inflammation to anti-inflammatory switch, hASC treatment restored a comprehensive efferocytic program involving multiple functional stages: chemotaxis (GPR132), recognition/engulfment (PARP9, ELMO1, RAC1), and lysosomal digestion/exhaution and polarisation (LAMP1, LIPA, PPAR-γ, ABCA1). This multi-targeted enhancement was accompanied contributed to the efficient clearance of apoptotic cells, reduced renal oxidative stress, and the mitigation of chronic inflammation.</p> Conclusions <p>Our study systematically delineates the therapeutic benefits of hASCs, suggesting the promotion of macrophage efferocytosis as a significant mechanistic pathway by which hASCs exert their therapeutic effects. Specifically, we demonstrate that hASCs positively regulate key molecular signatures across multiple stages of this process — from “find-me” signal (LPC/GPR132) and “eat-me” recognition (PS/ELMO1) to lysosomal digestion (LAMP1) and subsequent exhaustion and polarisation (LIPA/PPAR-γ/ABCA1).</p> Graphical Abstract <p></p>