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Reciprocal MDK-THRB lipid-oxidation transcriptional programs in MASH-associated hepatocellular carcinoma: a
V Muniappan1, Kalash Dwivedi2,3, S Sakila4
1Department of Anatomy, Shri Sathya Sai Medical College Research Institute, Sri Balaji Vidyapeeth Deemed to Be University, Puducherry, India.
Purpose:
Midkine (MDK) and thyroid hormone receptor beta (THRB) have each been implicated separately in metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). THRB drives hepatic fatty-acid beta-oxidation (FAO). We tested whether MDK and the THRB-linked FAO program are reciprocally related in human liver tissue.
Methods:
We analyzed two independent human cohorts on different platforms. TCGA-LIHC provided 374 tumor and 50 adjacent non-tumor RNA-seq samples. GSE164760 provided 53 NASH-HCC, 74 NASH, 29 non-tumoral NASH adjacent to HCC, 8 cirrhotic and 6 healthy microarray samples. We quantified MDK, THRB and a curated 21-gene hepatic FAO composite score. Tests included Mann-Whitney, Spearman, Kruskal-Wallis, Jonckheere-Terpstra and genome-wide correlation with Benjamini-Hochberg correction.
Results:
MDK was higher in tumor tissue in both cohorts (TCGA-LIHC p = 1.0 × 10-24, GSE164760 p = 8.1 × 10-13). The FAO composite was correspondingly lower (p = 7.0 × 10-10 and p = 7.1 × 10-6). THRB itself was lower in GSE164760 (p = 3.9 × 10-3) but not in TCGA-LIHC (p = 0.509). MDK correlated negatively with THRB and with the FAO composite in both cohorts. The strongest association was MDK versus FAO composite (rho=-0.45 in each cohort). Within-group analysis showed that the THRB to FAO composite correlation persisted in almost every subgroup. The MDK correlations weakened in three smaller subgroups. Across the five GSE164760 disease states, MDK, THRB and the FAO composite each differed significantly (Kruskal-Wallis p < 10-5) and each followed a significant monotonic trend (Jonckheere-Terpstra one-sided p < = 1.5 × 10-3).
Conclusion:
A reciprocal MDK-high and FAO-low transcriptional signature is reproducible across two independent human cohorts and across the MASH-to-HCC spectrum. These human tissue data support THRB agonism as a candidate therapeutic rationale in MASH-HCC that warrants prospective validation.
Supplementary Information:
The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05104-3.