In vivo, Entinostat suppressed tumor growth and consistently modulated the HDAC1/p53/AMPK/mTOR pathway. In conclusion, Entinostat exerts potent anti-tumor activity in SCLC by simultaneously inducing apoptosis and autophagy through epigenetic modulation of p53 via HDAC1 inhibition and subsequent regulation of the AMPK/mTOR axis.

P1/2, N=47, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2026 --> Feb 2027

Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.

Aggregated CMap analysis nominated histone deacetylase (HDAC) inhibition, with entinostat (MS-275) ranking highest as a candidate to reverse the high-risk transcriptomic program. An Arg-axis-anchored approach resolves biologically coherent NB subtypes and yields a parsimonious, fixed-coefficient four-gene signature that generalizes across cohorts, aligns with immune contexture, and proposes testable therapeutic hypotheses. These results support metabolism-informed risk stratification in NB and motivate prospective validation with standardized processing, mechanistic flux assays, and rational combination studies.

Entinostat, an inhibitor of class I HDAC, synergizes with cisplatin by preventing ARHGDIB delactylation. Collectively, our findings unveil a unique paradigm in which delactylation of tumor suppressors drives metastasis and chemoresistance. Targeting lactylation dynamics with HDAC inhibitors presents an avenue for intervention of bladder cancer.

P=N/A, N=50, Not yet recruiting, Sun Yat-sen University Cancer Center; Sun Yat-sen University Cancer Center

In conclusion, our work elucidates a coherent epigenetic pathway wherein entinostat activates AZGP1 to inhibit HCC metastasis. These findings nominate AZGP1 as both a critical mediator and a potential biomarker for entinostat-based therapy in advanced HCC.

P2, N=118, Recruiting, Zhejiang Cancer Hospital

Entinostat demonstrates strong anti-NSCLC activity by suppressing EGFR expression and downstream signaling, highlighting its potential as a therapeutic agent.

The short-term in vitro effects of 5d were modulated by a compensatory upregulation of autophagy. However, in long-term, this protective mechanism becomes insufficient to sustain tumor survival, resulting in strong antitumor efficacy in vivo in the CAM assay for both compounds even outperforming entinostat.

P1/2, N=49, Recruiting, National Cancer Institute (NCI) | N=30 --> 49

P1/2, N=55, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2025 --> Nov 2026