Dkk3, belonging to the DKK family, codes for an evolutionally conserved secreted glycoprotein. It functions as an antagonist of the oncogenic Wnt signaling pathway and has been implicated in multiple biological processes and diseases [3,6,7]. Genetic models like KO/CKO mouse models are valuable for studying its functions.

In muscle-related studies, myofiber-specific ablation of Baf60c in mice led to a robust upregulation of Dkk3, which inhibited muscle stem cell differentiation and attenuated muscle regeneration in vivo. Conversely, Dkk3 blockade promoted muscle regeneration and contraction, indicating Dkk3's role in muscle regeneration through paracrine signaling [1].

In renal fibrosis, knockdown of Dkk3 in UUO mice inhibited oxidative stress, maintained mitochondrial homeostasis, and alleviated kidney damage and fibrosis. Mechanistically, Dkk3 activated the Wnt/β -catenin pathway to increase MFF transcriptional expression, leading to mitochondrial dysfunction [2].

In head and neck squamous cell carcinoma (HNSCC), Dkk3 knockdown significantly decreased cell proliferation, migration, and invasion through decreased AKT phosphorylation, suggesting its oncogenic function in HNSCC [3].

In neuropathic pain, exogenous intrathecal administration of rDKK3 inhibited microglial activation-related signaling, promoted microglia transformation from M1 to M2 type, and decreased pro-inflammatory cytokines, ameliorating neuropathic pain [4].

In chronic obstructive pulmonary disease (COPD)-related sarcopenia, Dkk3 was overexpressed, and its inhibition prevented cigarette-smoking-induced skeletal muscle dysfunction, suggesting it as a potential diagnostic and therapeutic target [5].

In children with chronic kidney disease, urinary DKK3 above the median was associated with a greater 6-month eGFR decline, and it could help identify those who benefit from pharmacological nephroprotection [8].

In conclusion, Dkk3 plays diverse roles in multiple biological processes and disease conditions. Mouse models with Dkk3 knockout or knockdown have revealed its functions in muscle regeneration, renal fibrosis, cancer, neuropathic pain, sarcopenia in COPD, and kidney function decline in children. These findings contribute to understanding disease mechanisms and potentially developing new therapeutic strategies.