Lower MMP12 expression is likely to contribute to better effect of postoperative adjuvant transarterial chemoembolization via reducing MEK/ERK signaling activity in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) frequently recurs after hepatectomy. Transarterial chemoembolization (TACE) is a common adjuvant therapy; however, reliable indicators of its efficacy remain limited. This study aimed to evaluate the clinical significance of matrix metallopeptidase 12 (MMP12) in HCC patients undergoing postoperative adjuvant TACE (PA-TACE) and to explore potential strategies to enhance the efficacy of PA-TACE. A retrospective analysis was conducted on 225 HCC patients who received TACE and were categorized into prophylactic and recurrence TACE groups. Clinical data including liver function, tumor characteristics, and imaging findings were collected. Tissue samples were subjected to MMP12 immunohistochemical staining, and patients were further stratified according to MMP12 expression levels. Univariate and multivariate Cox regression analyses were performed to identify risk factors, and a nomogram was constructed for prognostic evaluation. The role of MMP12 in TACE for HCC was examined using Western blotting, RT-qPCR, mass spectrometry, Transwell, wound-healing, and colony formation assays. Kaplan-Meier curves demonstrated significantly better survival in the low-MMP12-expression group. Microvascular infiltration, alpha-fetoprotein (AFP) levels, and MMP12 expression were identified as independent risk predictors for survival. The nomogram derived from these factors exhibited high predictive accuracy (area under the curve: 0.750-0.959) across multiple time points. In vitro experiments revealed that targeting MMP12 inhibited HCC cell invasion, migration, and colony formation by blocking the MEK/ERK signaling pathway. The MMP12 inhibitor GM6001 enhanced the therapeutic effects of TACE. In conclusion, MMP12 was identified as a key and independent prognostic biomarker for PA-TACE in HCC patients. The prognostic model integrating MMP12, AFP, and microvascular infiltration may help identify patients most likely to benefit from PA-TACE. Targeting MMP12 to block the MEK/ERK pathway and suppress HCC cell malignancy highlights its potential as a therapeutic target to improve PA-TACE efficacy.