Objective To investigate the expression of opioid growth factor(OGF),OGF receptor(OGFR),P16,and P21 in elderly patients with colorectal cancer and their correlations with clinicopathological characteristics. Methods Bioinformatic analysis of OGFR was performed via differential expression analysis,survival analysis,single-cell RNA sequencing,and spatial transcriptomics.A total of 167 elderly patients with colorectal cancer were enrolled,with 30 fresh tissue samples collected from January 2023 to December 2024 and 137 paraffin-embedded tissue samples collected from January 2016 to January 2020.All the specimens were collected from confirmed cases at the First Affiliated Hospital of Hebei North University.OGF expression in the 30 fresh tissue samples was detected by ELISA,while the protein levels of OGFR,P16,and P21 were measured by Western blot.Immunohistochemistry was employed to assess OGFR,P16,and P21 expression in the 137 paraffin-embedded samples.SPSS 20.0 was used to analyze the correlations of OGFR,P16,and P21 expression with clinicopathological characteristics.The Spearman method was adopted to evaluate correlations among OGFR,P16,and P21 expression.Overall 5-year survival and differences between groups were assessed by Kaplan-Meier survival curves and the log-rank test. Results Differential expression analysis revealed that the expression of OGFR was upregulated in colorectal cancer tissue samples(P<0.001).Survival analysis revealed a significant correlation between high OGFR expression and poor prognosis(disease-free interval:P=0.019,disease-specific survival:P=0.015).Single-cell and spatial omics analyses indicated that OGFR was primarily expressed in tumor cells.ELISA results showed that compared with that in the adjacent normal tissue,the OGF expression levels elevated in pathological stages Ⅰ(P<0.001),Ⅱ(P=0.042),Ⅲ(P<0.001),and Ⅳ(P=0.001).Western blot results demonstrated that compared with that in the adjacent normal tissue,the protein level of OGFR was up-regulated in pathological stages Ⅰ(P<0.001),Ⅱ(P=0.047),Ⅲ(P=0.045),and Ⅳ(P=0.012).Compared with those in the adjacent normal tissue,the protein levels of P16 and P21 were down-regulated in pathological stages Ⅰ(P=0.001,P<0.001),Ⅱ(P=0.031,P=0.008),Ⅲ(P=0.026,P=0.024),and Ⅳ(P=0.018,P=0.015).Immunohistochemistry results demonstrated that OGFR had higher expression in cancer tissue samples than in adjacent normal tissue samples(P<0.001),and its expression level was correlated with T stage(P=0.047),lymph node metastasis(P=0.035),TNM stage(P=0.013),differentiation degree(P=0.043),and distant metastasis(P=0.030).Conversely,the protein levels of P16 and P21 were lower in cancer tissue samples(all P<0.001).P16 expression was correlated with T stage(P=0.009),lymph node metastasis(P=0.035),TNM stage(P=0.001),and differentiation degree(P=0.021).P21 expression showed correlations with T stage(P=0.009),lymph node metastasis(P=0.002),and TNM stage(P=0.046).The 5-year overall survival rate of the 137 elderly patients with colorectal cancer was 55.47%.The patients with positive expression of OGFR had a lower 5-year overall survival rate than those with negative expression(P=0.001).The patients with negative expression of P16 or P21 had a lower 5-year overall survival rate than those with positive expression(P16:P<0.001;P21:P=0.007). Conclusions In the colorectal cancer tissue of elderly patients,the expression of OGFR was negatively correlated with that of P16 and P21.The OGF-OGFR signaling pathway may promote colorectal cancer progression by suppressing P16 and P21 expression.The combined detection of these markers shows potential as a valuable reference for assessing disease progression.