Objective To investigate the relationship between serum high-mobility group box-1(HMGB-1)and glucose-regulated protein-78(GRP-78)levels and the severity of coronary artery lesions and myocardial fibrosis(MF)in patients with acute coronary syndrome(ACS).Methods A total of 155 ACS patients(ACS group)admitted to the hospital from January 2021 to August 2024 and 70 healthy volunteers who came to the hospital for health check ups during the same period(control group)were enrolled.ACS patients were further categorized based on the severity of coronary artery lesions(SYNTAX Ⅱ score)into mild lesion group(65 cases),moderate lesion group(51 cases),and severe lesion group(39 cases).Additionally,they were divided into the MF group(62 cases)and the non-MF group(93 cases)based on whether MF was present.Serum HMGB-1 and GRP-78 levels were measured using enzyme-linked immunosorbent assay.The correlation be-tween serum HMGB-1 and GRP-78 levels and SYNTAX Ⅱ score was assessed using Spearman's rank correla-tion.Multivariate Logistic regression analysis was used to identify factors influencing MF in ACS patients.Re-ceiver operating characteristic(ROC)curve was used to evaluate the value of serum HMGB-1 and GRP-78 levels in diagnosing severe coronary artery lesions and MF.Results Serum HMGB-1 and GRP-78 levels were significantly higher in the ACS group compared to the control group(P<0.05).The serum levels of HMGB-1 and GRP-78 increased sequentially in the mild,moderate,and severe lesion groups(P<0.05).Serum HMGB-1 and GRP-78 levels were positively correlated with SYNTAX Ⅱ score(P<0.05).Serum HMGB-1 and GRP-78 levels in the MF group were significantly higher than those in the non-MF group(P<0.05).High SYNTAX Ⅱ score,high N-terminal pro-brain natriuretic peptide,high HMGB-1,and high GRP-78 were independent risk factors for MF in ACS patients(P<0.05).The area under the curve for the combined detec-tion of serum HMGB-1 and GRP-78 levels for the diagnosis of severe coronary artery lesions in ACS patients was 0.887,which was larger than those of serum HMGB-1(0.803)and GRP-78(0.791)alone(P<0.05).The area under the curve of the combined detection of serum HMGB-1 and GRP-78 levels for the diagnosis of MF in ACS patients was 0.882,which was larger than those of serum HMGB-1(0.797)and GRP-78(0.789)alone(P<0.05).Conclusion Serum HMGB-1 and GRP-78 levels are elevated in ACS patients and are closely associated with the severity of coronary artery lesions and MF.The combined detection of serum HMGB-1 and GRP-78 levels has high value in diagnosing severe coronary artery lesions and MF in ACS patients.