Plod2, encoding lysyl hydroxylases 2, is a key enzyme mediating the formation of stabilized collagen cross-links, thus playing a vital role in the assembly of the extracellular matrix (ECM) [1]. It has been implicated in various biological processes and disease conditions, especially cancer-related pathways.

In clear cell renal cell carcinoma (ccRCC), hypoxia-induced PLOD2 promotes cancer progression by interacting with EGFR, phosphorylating the receptor, and activating the AKT signaling pathway [2]. In osteosarcoma, APLN upregulates PLOD2 expression via the Hippo signaling pathway and hsa_circ_0000004/miR-1303 axis, enhancing cell migration and metastasis [3]. In glioblastoma, high levels of PLOD2 are associated with poor overall survival, and its knockdown inhibits tumor proliferation, invasion, and anchorage-independent growth, while also modulating the immune microenvironment by inducing neutrophils to acquire a pro-tumor phenotype [4]. In osteosarcoma, PLOD2 promotes cell migration, invasion, and angiogenesis both in vitro and in vivo, and is associated with immune cell infiltration [5]. In colorectal cancer, PLOD2 stabilizes USP15 to activate the AKT/mTOR signaling pathway, facilitating cancer progression [6]. In hepatocellular carcinoma, PLOD2 is upregulated in advanced tumors, and its knockdown reduces cell migration, invasion, and metastasis in mouse models [7]. In cervical cancer, high PLOD2 expression is related to poor prognosis and is correlated with immune cell infiltration [8]. In a mouse model of heterotopic ossification, the HIF-1α/PLOD2 axis links extracellular matrix organization and cell metabolism, and inhibiting PLOD2 activity decreases osteogenic differentiation and glycolytic metabolism [9]. In varicocele rats, oxidative stress promotes PLOD2 expression via m6A methylation modification, and targeted demethylation affects GC-2 cell proliferation and apoptosis [10].

In conclusion, Plod2 is essential for collagen cross-linking and ECM organization. Through various in vivo and functional studies, especially in KO/CKO mouse models or loss-of-function experiments, it has been shown to play a significant role in cancer progression, immune infiltration, and aberrant musculoskeletal repair. Understanding Plod2's functions provides potential targets for treating related diseases.