The Mechanism of Mg²⁺-Mediated Inhibition of Cervical Cancer by Inducing a Senescence-like State via the ATM/CHK2/p21 Signaling Pathway

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model.