rocilinostat (ACY-1215) / Regenacy, BMS, BC Regenacy - LARVOL DELTA

HDAC6 is involved in diabetic nephropathy by regulating TGFβ/Smads and NF-κB signaling pathways. (PubMed, Biochem Pharmacol) - "Our research indicates that HDAC6 is upregulated in DN, and inhibiting HDAC6 activity with ACY1215 or downregulating HDAC6 expression with siRNA can suppress the TGF-β/Smads and NF-κB signaling pathways, thereby reducing renal fibrosis and inflammation...To sum up, this study reveals that HDAC6 is involved in the pathogenesis and progression of DN. Mechanistically, HDAC6 may participate in DN by regulating the TGF-β/Smads and NF-κB signaling pathways through Smad7."

Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • HDAC6 • SMAD2 • SMAD7 • TGFB1

IDH1/MDH1 deacetylation activates the cGAS-STING pathway by promoting NETosis in acute liver failure. (PubMed, Int Immunopharmacol) - "IDH1/MDH1 deacetylation activates the cGAS-STING signaling pathway by NETs. The activation of STING promotes pro-inflammatory cytokine production and exacerbates the inflammatory response in LPS/D-gal-induced ALF."

Journal • Hepatology • Inflammation • Liver Failure • IDH1 • IL6 • TNFA

Inhibition of histone deacetylase 6 activity mitigates neurological impairment and post-hemorrhagic hydrocephalus after intraventricular hemorrhage by modulating pyroptosis and autophagy pathways. (PubMed, Fluids Barriers CNS) - "Enhanced autophagy attenuates activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and inhibits neuronal pyroptosis in the acute phase of IVH. HDAC6 plays an important role in regulating the interaction between autophagy and pyroptosis. Ricolinostat treatment significantly attenuated the upregulation of inflammatory factors and neurological impairments induced by pyroptosis in the acute phase of IVH. In addition, ricolinostat effectively reduced excessive autophagy and apoptosis in neurons in the chronic phase and attenuated the formation of PHH."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Ventriculomegaly • NLRP3

Histone deacetylase 6 inhibition abrogates the STAT3-mediated protumoral polarization of M2 TAMs and suppresses the VEGFA/VEGFR2-induced macrophage-breast cancer crosstalk in the tumor microenvironment (ESMO-BC 2025) - "The data was validated in a syngeneic murine breast cancer model. ACY1215 a first-in-class inhibitor of HDAC6, abrogates protumoral polarization of M2 TAMs... Our data suggests HDAC6 plays a pivotal role in driving the protumoral polarization of M2 TAMs. Upon its inhibition, the prometastatic potential of M2 TAMs decreases, disrupting their crosstalk with the breast cancer cells in the TME."

Biomarker • Epigenetic controller • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • BRCA • CD163 • IL13 • IL4 • KDR • MRC1 • MYC • STAT3

HDAC6 inhibition ameliorates sensory hypersensitivity and reduces immune cell signatures in the dorsal root ganglia in murine chronic pain models. (PubMed, Mol Pharmacol) - "SIGNIFICANCE STATEMENT: Recent studies highlight the role of histone deacetylase (HDAC)6 in chemotherapy-induced peripheral neuropathy, through mechanisms of action including tubulin acetylation and mitochondrial trafficking. In this study, various murine models of acute and chronic pain are applied to show that inhibition of HDAC6 activity in the periphery, using the clinically tested ACY1215 compound, and genetic inactivation of the Hdac6 gene in the dorsal root ganglia, alleviated mechanical hypersensitivity in male and in female mice through mechanisms that include targeting injury-induced inflammation."

Journal • Preclinical • Immunology • Inflammation • Neuralgia • Pain • Peripheral Neuropathic Pain • HDAC6

Withaferin A combined with ricolinostat: a potent synergistic therapy for cervical cancer through regulating p53 ubiquitination and acetylation. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - No abstract available

Journal • Cervical Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Histone deacetylase 6 inhibitor affects gut microbiome composition in alcoholic liver mice (APASL 2025) - "By analyzing the gut microbiome of mice, we found that the effects of alcohol and the HDAC6 inhibitor ACY1215 on the composition of the mouse gut microbiome were significant, with some changes in the gut microbiome related to both glucose and lipid metabolism. This sheds some light on the systemic changes caused by HDAC6 inhibitors in vivo and may be involved in the progression of alcohol associated liver disease. Table and Figure:Figure 1.KEGG heatmap Figure 2.eggNOG heatmap"

Epigenetic controller • Preclinical • Hepatology • Infectious Disease • Metabolic Disorders

HDAC6 Inhibitor ACY-1215 Improves Gefitinib-lnduced Liver Injury via Inhibiting TLR4/MyD88/MAPK/ NF-kB Pathway (APASL 2025) - "ACY-1215 could partially reverse the gefitinib-induced liver injury and dysfunction by inhibiting the TLR4/MyD88/MAPK/NFκB signaling pathway. Table and Figure:Figure 1.AML 12 and MIHA cells were co-cultured with 30μM gefitinib and different concentrations of ACY1215 for 24 hours. (A) Cell viability."

Hepatology • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL6 • MYD88 • NFKBIA • TLR4 • TNFA

Inhibition of histone deacetylase 6 alleviates neuropathic pain via direct regulating post-translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis. (PubMed, J Neuroinflammation) - "These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management."

Journal • Immunology • Neuralgia • Oncology • Pain • HDAC6 • IL1B • STAT3 • TNFA

VHL ameliorates arecoline-induced oral submucosal fibrosis by promoting HDAC6 ubiquitination and blocking NF-κB pathway. (PubMed, Sci Rep) - "HDAC6 selective inhibitor ACY-1215 inhibited the NF-κB signaling pathway. VHL attenuated arecoline-induced OSF by inhibiting the ubiquitination of HDAC6 and blocking NF-κB pathway. As a result, our study offers new perspectives into the discovery of novel tactics that can be employed against OSF."

Journal • Fibrosis • Immunology • Oncology • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • HDAC6

Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis. (PubMed, Life Sci) - "Our findings recognized the HDAC6/Hint2/MICU1 axis as a novel pathway in neutrophils, the inhibition of which intercepts mCa2+ overload and mtROS accumulation, thereby reducing NETosis and facilitating liver recovery during ALF."

Journal • Hepatology • Inflammation • Liver Failure

Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy. (PubMed, J Med Chem) - "Moreover, HP29 exhibited significant in vivo antitumor efficacy in a melanoma tumor model with a greater tumor growth inhibition (TGI) (65.5%) than that of NP19 (43.2%), ACY-1215 (45.6%), and the combination group (53.9%). Mechanistically, the percentages of tumor-infiltrating lymphocytes (TILs) in the HP29-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, HP29 represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential cancer immunomodulating agent."

Journal • PK/PD data • Melanoma • Oncology • Solid Tumor

Polymer-based nanodrugs enhance sonodynamic therapy through epigenetic reprogramming of the immunosuppressive tumor microenvironment. (PubMed, J Control Release) - "In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric)...Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HDAC6 • TGFB1

ACY1215 Exerts Anti-inflammatory Effects by Inhibition of NF-κB and STAT3 Signaling Pathway to Repair Spinal Cord Injury. (PubMed, Biol Pharm Bull) - "In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI."

Journal • CNS Disorders • Oncology • Orthopedics • GFAP • IL1B • IL6 • TNFA

IDH1/MDH1 deacetylation promotes NETosis by regulating OPA1 and autophagy. (PubMed, Int Immunopharmacol) - "IDH1/MDH1 deacetylation promoted NETosis by regulating autophagy and OPA1 in vitro. The regulation of neutrophil autophagy on NETosis during IDH1/MDH1 deacetylation might be masked in mice. ACY1215 might attenuate NETosis by regulating neutrophil autophagy, which alleviated ALF aggravated by IDH1/MDH1 deacetylation."

Journal • Hepatology • Liver Failure • BECN1 • IDH1

Ricolinostat, an HDAC6 inhibitor, suppresses hypoxia-induced responses and M2 polarization of macrophages in triplenegative breast cancer by modulating HIF-1α pathway (KSMO 2024) - No abstract available

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HIF1A

ClassIIb histone deacetylase participates in perioperative neurocognitive disorders in elderly mice via HSP90/GR signaling pathway. (PubMed, Exp Neurol) - "Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery."

Epigenetic controller • Journal • Preclinical • Anesthesia • CNS Disorders • Cognitive Disorders • Developmental Disorders • CDC37 • HSP90AA1

ACY-1215 for Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=23 | Terminated | Sponsor: Jennifer Amengual | Completed ➔ Terminated; Lack of funding

Trial termination • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology

ACY-1215 (Ricolinostat) in Combination With Pomalidomide and Low-dose Dex in Relapsed-and-Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=103 | Terminated | Sponsor: Celgene | Active, not recruiting ➔ Terminated; Lack of efficacy

Combination therapy • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway. (PubMed, Heliyon) - "ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway."

Journal • Hepatology • Liver Failure • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • CD14 • IL1B • MYD88 • TLR4 • TNFA

Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain. (PubMed, J Med Chem) - "Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development."

Journal • Inflammation • Pain

Downregulation of HDAC6 mitigates lung ischemia/reperfusion injury depending on activation of Nrf2/HO-1 signaling pathway and inactivation of ERK/NF-κB signaling pathway. (PubMed, Tissue Cell) - "HDAC6 inhibition may mitigate H/R-induced lung epithelial cell injury depending on activation of Nrf2/HO-1 signaling pathway and inactivation of ERK/NF-κB signaling pathway."

Journal • Cardiovascular • Inflammation • Metabolic Disorders • Reperfusion Injury • HDAC6

Inhibition of HDAC6 attenuates M2 polarization of macrophages by breast cancer cells in hypoxic tumor microenvironment (EACR 2024) - P1/2 | "Material and Methods Breast cancer cells were maintained under hypoxic conditions for 48h, followed by treatment with vehicle or ricolinostat, an oral first in class isoform-selective inhibitor of HDAC6 under clinical trials [NCT02091063]...Conclusion Selective inhibition of HDAC6 in hypoxic breast cancer cells abrogates hypoxia induced AKT/STAT3/Cmyc signaling, and diminishes their potential to polarize monocytes into M2 TAMs, altering the immunosuppressive properties of the tumor microenvironment. HDAC6 inhibition stands as a promising approach to treat metastatic aggressive breast cancer."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • HIF1A • HSP90AA1

Deacetylated MDH1 and IDH1 aggravates PANoptosis in acute liver failure through endoplasmic reticulum stress signaling. (PubMed, Cell Death Discov) - "The deacetylation weakened the inhibitory effect of histone deacetylase (HDAC) inhibitor ACY1215 on PANoptosis-related molecules, suggesting that deacetylated MDH1 at K118 and IDH1 at K93 aggravated PANoptosis during ALF...The results suggested that deacetylated MDH1 at K118 and IDH1 at K93 may aggravate PANoptosis in ALF through endoplasmic reticulum stress signaling. In conclusion, deacetylated MDH1 and IDH1 may aggravate PANoptosis in ALF, and the mechanism may act through endoplasmic reticulum stress signaling."

Journal • Hepatology • Liver Failure • ATF6 • CASP3 • IDH1 • IL18 • IL1B • RIPK1 • XBP1

HBV promotes viral replication and autophagic secretion through HBx down-regulation of HDAC6 expression (EASL-ILC 2024) - "Transcription of virus-associated RNA and replication of HBV DNA were found to be significantly enhanced after the use of HDAC6 selective inhibitor (ACY1215). HBV promotes viral replication and autophagic secretion through HBx down-regulation of HDAC6 expression."

Hepatitis B • Hepatology • Inflammation • HDAC6