The widespread use of PD-1 inhibitors in cancer therapy has made thyroid dysfunction one of the commonly observed adverse events associated with this treatment. Glycyrrhizin-based hepatoprotective drugs are extensively used in oncology, yet whether they influence the development of PD-1 inhibitor-related thyroid dysfunction remains unclear. Investigating the relationship between the two holds significant implications for optimizing the safety management of immunotherapy.

To investigate the effect of glycyrrhizin-containing hepatoprotective agents on the risk of thyroid dysfunction in cancer patients receiving PD-1 inhibitor therapy.

A retrospective cohort study was conducted, including 175 cancer patients with normal baseline thyroid function who received PD-1 inhibitor therapy at the Third People's Hospital of Zhengzhou from January 2021 to July 2023. Patients were divided into a medication group (62 cases, using glycyrrhizin-containing hepatoprotective agents) and a control group (113 cases) based on whether they prophylactically used glycyrrhizin-based hepatoprotective agents. Baseline data of patients, including demographic information and clinical examination indicators were collected. Follow-up began at the first administration of a PD-1 inhibitor, during which glycyrrhizin-based hepatoprotectants were prophylactically used. The timing of PD-1 inhibitor administration was recorded, and thyroid function indicators including free triiodothyronine (FT₃), free thyroxine (FT₄), thyroid-stimulating hormone (TSH) were regularly monitored throughout the period. The cutoff date for follow-up was July 2025, and the outcome measure was the occurrence of thyroid dysfunction in patients. The incidence of thyroid dysfunction was assessed using the Kaplan-Meier method. Variable selection was performed using Lasso regression, and risk factors for thyroid dysfunction were analyzed using multivariate Cox regression. SHAP values assessed factor contributions, E-values evaluated unmeasured confounding, and sensitivity analysis was performed using inverse probability weighting.

The time at which the cumulative probability of remaining free of thyroid dysfunction reached 50% was 2.5 months (95%CI=1.5-3.5) in the medication group and 8.0 months (95%CI=6.0-10.0) in the control group. The difference was statistically significant (P<0.001). Multivariate Cox regression analysis showed that the use of glycyrrhizic acid-based hepatoprotective drugs (HR=1.774, 95%CI=1.032-3.051, P=0.038), gastrointestinal tumors (HR=2.223, 95%CI=1.096-4.509, P=0.027), other tumor types (HR=2.320, 95%CI=1.093-4.920, P=0.028), and combined tyrosine kinase inhibitor therapy (HR=1.923, 95%CI=1.077-3.434, P=0.027) were independent influencing factors for thyroid dysfunction in patients. SHAP value analysis revealed that concomitant use of tyrosine kinase inhibitors (0.741) and glycyrrhizin-containing hepatoprotective drugs (0.381) were the most significant predictors of thyroid dysfunction. The E-value was 2.33, and sensitivity analyses yielded consistent results with the primary analysis.

Glycyrrhizin-containing hepatoprotective drugs may increase the risk of thyroid dysfunction in cancer patients undergoing PD-1 inhibitor therapy. Clinicians should exercise caution when co-administering these hepatoprotective agents with PD-1 inhibitors and implement enhanced monitoring of thyroid function in such patients.