LGALS3 is an efferocytosis-related biomarker and potential traditional Chinese medicine therapeutic target for diabetic kidney disease complicated with heart failure

To explore the immune efferocytosis mechanisms of diabetic kidney disease (DKD) complicated with chronic heart failure (CHF) in light of the glucose heart kidney axis and predict the "same treatment for different diseases" strategy using traditional Chinese medicine (TCM).

DKD and CHF transcriptome data from public databases were integrated to construct a core gene set using differential expression and weighted gene co-expression network analysis (WGCNA). The hub genes were intersected with an efferocytosis-related gene set, validated with external datasets, and functionally enriched. The Coremine Medical database and molecular docking were used to predict the regulatory TCMs, their properties, and affinities between the active ingredients and their targets. Clinical serum samples were collected form patients with DKD, CHF, and DKD+CHF and healthy individuals for detecting galectin 3 (LGALS3) levels.

Fifty comorbidity core genes were identified, which were enriched mainly in the PI3K Akt, TNF, AGE RAGE, and oxidative phosphorylation pathways. LGALS3 was identified as a key efferocytosis-associated hub gene with differential expression in the validation set. The prediction results included 216 TCMs predominantly exhibiting cold or warm properties with bitter, sweet or pungent flavors and liver, lung, spleen and kidney meridian tropisms. Molecular docking suggested strong binding between the key ingredients (e.g., quercetin) and LGALS3. Serum LGALS3 levels were significantly higher in patients with DKD+CHF than in those with DKD or CHF alone or healthy controls (all P<0.001). After adjusting for covariates, comorbid status remained independently and positively associated with LGALS3 (β =51.20, P<0.001), exceeding the independent contribution of NT proBNP.

DKD-CHF is associated with inflammatory/metabolic abnormalities and impairment of efferocytosis-mediated immune clearance. LGALS3 is a critical node connecting inflammatory pathways to target organ efferocytosis dysfunction. The predicted TCMs highlight the TCM therapeutic principles of "supplementing Qi, clearing the heat and resolving stasis" and may regulate efferocytosis and the immunometabolic microenvironment by targeting LGALS3.