Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras.

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.

A non-antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti-fatigue protein orosomucoid in mice.

At present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti-fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS-01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS-01 could time- and dose-dependently prolong mice forced-swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS-01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm-deficient mice, the anti-fatigue and glycogen-elevation activity of HMS-01 disappeared. Therefore, HMS-01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Swimming exercise ameliorates insulin resistance and nonalcoholic fatty liver by negatively regulating PPARγ transcriptional network in mice fed high fat diet.

BACKGROUND: Recent findings elucidated hepatic PPARγ functions as a steatogenic-inducer gene that activates de novo lipogenesis, and is involved in regulation of glucose homeostasis, lipid accumulation, and inflammation response. This study delved into a comprehensive analysis of how PPARγ signaling affects the exercise-induced improvement of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD), along with its underlying mechanism. METHODS: Chronic and acute swimming exercise intervention were conducted in each group mice. IR status was assessed by GTT and ITT assays. Serum inflammatory cytokines were detected by Elisa assays. PPARγ and its target genes expression were detected by qPCR assay. Relative protein levels were quantified via Western blotting. ChIP-qPCR assays were used to detect the enrichment of PPARγ on its target genes promoter. RESULTS: Through an exploration of a high-fat diet (HFD)-induced IR and NAFLD model, both chronic and acute swimming exercise training led to significant reductions in body weight and visceral fat mass, as well as hepatic lipid accumulation. The exercise interventions also demonstrated a significant amelioration in IR and the inflammatory response. Meanwhile, swimming exercise significantly inhibited PPARγ and its target genes expression induced by HFD, containing CD36, SCD1 and PLIN2. Furthermore, swimming exercise presented significant modulation on regulatory factors of PPARγ expression and transcriptional activity. CONCLUSION: The findings suggest that swimming exercise can improve lipid metabolism in IR and NAFLD, possibly through PPARγ signaling in the liver of mice.

Kinetic Resolution of ß-Alkyl Phenylethylamine Derivatives through Palladium-Catalyzed, Nosylamide-Directed C-H Olefination.

Palladium-catalyzed C-H activation reactions have attracted the attention of organic researchers due to their unique high selectivity, broad functional group tolerance, and high efficiency, and they are widely used in natural products and asymmetric synthesis. Here, we report an example of enantioselective C-H alkenylation between ß-alkyl phenylethylamine compounds and styrenes with Boc-L-lle-OH as the ligand and nosylamide as the directing group. This reaction is applicable to styrene containing various electron-deficient and electron-donating substitutions and may be utilized for the synthesis of benzoazepine compounds.

Modulation of top-down influence affects trafficking of glutamatergic receptors in the primary visual cortex.

Numerous studies indicate that top-down influence plays critical roles in visual perception by enhancing neuronal excitability in the primary visual cortex (V1). The underlying mechanisms are poorly understood. This study examined changes of excitatory glutamatergic markers in the V1 cortex of cat after top-down influence of cortical area 7 (A7) was modulated by transcranial direct current stimulation (tDCS). Our results showed that the content of glutamate as well as the total cellular protein of glutamatergic receptors, including the key subunit GluA1 of AMPA receptors and subunit NR1 of NMDA receptors, in the V1 cortex had no significant change after anode- and cathode-tDCS relative to sham-tDCS in A7. However, the plasma membrane protein content of GluA1 and NR1 in the V1 was significantly increased after anode-tDCS, but decreased after cathode-tDCS when compared with that after sham-tDCS in A7. Further, the abundance of phosphorylated GluA1 and NR1 in the V1 also elevated significantly after anode-tDCS, but lowered after cathode-tDCS compared with that after sham-tDCS. Additionally, the content of phosphorylated CaMKII (p-CaMKII), a protein kinase preferentially boosting phosphorylation of glutamatergic receptors, in the V1 improved after anode-tDCS although no significant alteration occurred after c-tDCS in A7. Taken together, our results indicate that feedback influence of A7 may facilitate the trafficking of glutamatergic receptors to postsynaptic membrane in the V1 cortex through receptors' phosphorylation process, which could be an important mechanism of high-level cortex in modulating visual information processing in the V1 cortex.

Exercise ameliorates insulin resistance and improves ASK1-mediated insulin signalling in obese rats.

Increasing evidence reveals that physical exercise is an efficient therapeutical approach in the treatment of insulin resistance (IR) and related metabolic diseases. However, the potential beneficial effects of exercise on insulin resistance and its underlying mechanisms remain unclear. Recent findings elucidated the negative role of ASK1 in repressing the glucose uptake through JNK1-IRS1-Akt signalling in liver. Thus, a detailed investigation of the effect of ASK1-mediated insulin signalling on exercise-mediated improvement of insulin sensitivity and its underlying mechanism was implemented in this study. Using a high-fat diet-induced IR rat model of chronic or acute swimming exercise training, we here showed that body weight and visceral fat mass were significantly reduced after chronic exercise. Moreover, chronic exercise reduced serum FFAs levels and hepatic triglyceride content. Both chronic and acute exercise promoted glucose tolerance and insulin sensitivity. Meanwhile, both chronic and acute exercise decreased ASK1 phosphorylation and improved JNK1-IRS1-Akt signalling. Furthermore, exercise training decreased CFLAR, CREG and TRAF1 protein levels in liver of obese rats, which are positive regulator of ASK1 activity. These results suggested that swimming exercise demonstrated to be an effective ameliorator of IR through the regulation of ASK1-mediated insulin signalling and therefore, could present a prospective therapeutic mean towards the treatment of IR and several metabolic diseases based on IR, containing NAFLD and type Ⅱ diabetes.

Structure-based design of glycyrrhetinic acid derivatives as potent anti-sepsis agents targeting high-mobility group box-1.

Novel Glycyrrhetinic Acid (GA) derivatives with fused heterocycles on A ring were structure-based designed and synthesized. Their potential anti-inflammatory effects were investigated by a classical LPS stimulated macrophage model. Surface plasmon resonance (SPR) was used to verify the binding of GA analogues with HMGB1. A preliminary structure-activity relationship was summarized and an analogue GA-60 with ortho-methoxybenzyl pyrozole showed stronger anti-inflammatory effect and higher affinity for HMGB1 with a Kd value of 12.5 µM. In addition, this compound exhibited excellent inhibitory functions on NO (96%), TNF-α (94%), and IL-6 (100%), by interfering with phosphorylation of p38, ERK, JNK MAPKs, as well as that of NF-κB p65 and IKKα/ß. Moreover, GA-60 extended the survival of either the classic CLP-induced or LPS-induced sepsis mouse models. Molecular modeling predictions further supported these findings, clearly indicating that inhibiting HMGB1 release, using fused heterocyclic GA derivatives, is a promising strategy for treatment of sepsis.

Exercise ameliorates insulin resistance and improves SIRT6-mediated insulin signaling transduction in liver of obese rats.

Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6) - mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR.

Exercise ameliorates insulin resistance via regulating TGFß-activated kinase 1 (TAK1)-mediated insulin signaling in liver of high-fat diet-induced obese rats.

Exercise is an effective therapy for insulin resistance. However, the underlying mechanism remains to be elucidated. Previous research demonstrated that TGFß-activated kinase 1 (TAK1)-dependent signaling plays a crucial character in hepatic insulin resistance. Hepatic ubiquitin specific protease 4 (USP4), USP18, and dual-specificity phosphatases 14 (DUSP14) can suppress TAK1 phosphorylation, besides tumor necrosis factor receptor-associated factor 3 (TRAF3) and tripartite motif 8 (TRIM8) promote its phosphorylation. In this study, we tried to verify our hypothesis that exercise improves insulin resistance in high-fat diet (HFD)-induced obese (DIO) rats via regulating the TAK1 dependent signaling and TAK1 regulators in liver. Forty male Sprague-Dawley rats were randomized into four groups (n = 10): standard diet and sedentary as normal control; fed on HFD and DIO-sedentary; fed on HFD and DIO-chronic exercise; and fed on HFD and DIO-acute exercise. HFD feeding resulted in increased body weight, visceral fat mass, serum FFAs and hepatic lipid deposition, but decreased hepatic glycogen content and insulin sensitivity. Moreover, hepatic TRAF3 and TRIM8 protein levels increased, whereas USP4, USP18, and DUSP14 protein levels were decreased under obese status, which resulted in enhanced TAK1 phosphorylation and impaired insulin signaling. Exercise training, containing chronic and acute mode, both ameliorated insulin resistance. Meanwhile, decreased TAK1, c-Jun N-terminal kinase 1 (JNK1), and insulin receptor substrate 1 (IRS1) phosphorylation enhanced Akt phosphorylation in liver. Moreover, exercise enhanced USP4 and DUSP14 protein levels, whereas decreased TRIM8 protein levels in obese rats' liver. These results showed that exercise triggered a crucial modulation in TAK1-dependent signaling and its regulators in obese rats' liver, and distinct improvement in insulin sensitivity, which provide new insights into the mechanism by which physical exercise improves insulin resistance.

[Effect of swimming exercise on MEK and ERK1 phosphorylation level in adipose tissue of insulin resistance rats].

OBJECTIVE: To investigate the effect of chronic and acute swimming exercise intervention on the mitogen-activated extracellular signal-regulated kinase(MEK) and extracellular signal-regulated kinase 1(ERK1) phosphorylation level in adipose tissues of obesityinduced insulin resistance rats. METHODS: A total of 100 SD rats were randomly divided into control group(n=10) fed with normal diet and high-fat diet group(n=90) fed with high fat diet. After 8 weeks, one third rats(n=30) with upper weight in high-fat diet group were selected and randomly divided into high-fat diet sedentary group(n=10), chronic exercise group(n=10) and acute exercise group(n=10). Under another 8-week high-fat diet feeding, exercise intervention was performed according to the exercise procedure; control group was fed with normal diet for 8 weeks. After exercise intervention, visceral adipose tissues were separated and MEK and ERK1 phosphorylation level in adipose tissue was detected by Western blot method. RESULTS: Chronic exercise intervention significantly reduced body weight, visceral fat weight and visceral fat weight/body weight ratio(P<0. 01), and acute exercise intervention had no significant effect on body weight, visceral fat weight and visceral fat weight/body weight ratio. Both chronic and acute exercise intervention significantly increased body insulin sensitivity(P<0. 05), as well as significantly decreased MEK and ERK1 phosphorylation level in adipose tissues(P<0. 01). CONCLUSION: The improvement of obesity-induced insulin resistance by exercise might be related to inhibited phosphorylation of MEK and ERK1 in adipose tissues.

Synthesis, preliminary bioevaluation and computational analysis of caffeic acid analogues.

A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification.

[Effects of exercise and diet intervention on oxidative stress in insulin resistant rat].

OBJECTIVE: To investigate the effects of exercise, diet and their combination intervention on oxidative stress of insulin resistance rat. METHODS: Establish obesity-induced insulin resistance rat models. Obesity was assessed by the body weight and lipid ratio. Glucose tolerance was assessed by the integrated area under the curve for glucose (AUCg) during an oral glucose tolerance test (OGTT), then 8 weeks of exercise, diet, and combination interventions, respectively. To analyze serum free fatty acids (FFA) content, superoxide dismutase (SOD) and maleic dialdehyde (MDA) content in liver, adipose tissue and soleus muscle by biochemical method. Judge oxidative stressby FFA content and SOD/MDA. RESULTS: Three kinds of intervention reduced the body weight (P < 0.01), lipid ratio (P < 0.01) and AUCg (P < 0.01). Dietary and combination intervention lowered serum free fatty acid concentration (P < 0.01), separate exercise intervention had not such effect. Three kinds of intervention increased SOD/MDA in the liver and adipose tissue, exercise and combination intervention improved SOD/MDA in soleus muscle, dietary intervention alone had not the effect. CONCLUSION: Exercise and dietary intervention may improve the overall insulin resistance by alleviating oxidative stress.

Delivery of neurotrophin-3 by RVG-Lamp2b-modified mesenchymal stem cell-derived exosomes alleviates facial nerve injury.

We aim to investigate the effect of RVG-Lamp2b-modified exosomes (exos) loaded with neurotrophin-3 (NT-3) on facial nerve injury. Exos were collected from control cells (Ctrl Exo) or bone marrow mesenchymal stem cells co-transfected with RVG-Lamp2b and NT-3 plasmids (RVG-NT-3 Exo) by gradient centrifugation and identified by western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Effect of RVG-NT-3 Exo on oxidative stress damage was determined by analysis of the morphology, viability, and ROS production of neurons. Effect of RVG-NT-3 Exo on facial nerve axotomy (FNA) was determined by detecting ROS production, neuroinflammatory reaction, microglia activation, facial motor neuron (FMN) death, and myelin sheath repair. Loading NT-3 and modifying with RVG-Lamp2b did not alter the properties of the exos. Moreover, RVG-NT-3 Exo could effectively target neurons to deliver NT-3. Treatment with RVG-NT-3 Exo lowered H2O2-induced oxidative stress damage in primary neurons and Nsc-34 cells. RVG-NT-3 Exo treatment significantly decreased ROS production, neuroinflammatory response, FMN death, and elevated microglia activation and myelin sheath repair in FNA rat models. Our findings suggested that RVG-NT-3 Exo-mediated delivery of NT-3 is effective for the treatment of facial nerve injury.

Ferritinophagy induced ferroptosis in the management of cancer.

BACKGROUND: Ferroptosis, a newly form of regulated cell death (RCD), is characterized by iron dyshomeostasis and unrestricted lipid peroxidation. Emerging evidence depicts a pivotal role for ferroptosis in driving some pathological processes, especially in cancer. Triggering ferroptosis can suppress tumor growth and induce an anti-tumor immune response, denoting the therapeutic promises for targeting ferroptosis in the management of cancer. As an autophagic phenomenon, ferritinophagy is critical to induce ferroptosis by degradation of ferritin to release intracellular free iron. Recently, a great deal of effort has gone into designing and developing anti-cancer strategies based on targeting ferritinophagy to induce ferroptosis. CONCLUSION: This review delineates the regulatory mechanism of ferritinophagy firstly and summarizes the role of ferritinophagy-induced ferroptosis in cancer. Moreover, the strategies targeting ferritinophagy to induce ferroptosis are highlighted to unveil the therapeutic value of ferritinophagy as a target to manage cancer. Finally, the future research directions on how to cope with the challenges in developing ferritinophagy promoters into clinical therapeutics are discussed.

Clinical value of multiband mucosectomy for the treatment of squamous intraepithelial neoplasia of the esophagus.

BACKGROUND AND AIM: To evaluate the clinical value of multiband mucosectomy (MBM) for the treatment of squamous intraepithelial neoplasia of the esophagus. METHODS: A total of 51 lesions located at esophagus from 43 patients were treated with MBM, among which 11 were diagnosed as middle-grade intraepithelial neoplasia, 25 as high-grade intraepithelial neoplasia, and 15 as early esophageal cancer pathologically. Primary end-points were the rate of complete endoscopic resection and the mean operation time; the second end-points were the postoperative local recurrence rate and acute plus early complications. The histopathological results were compared between pre-MBM biopsy and MBM specimens. All patients were followed up endoscopically. RESULTS: A total of 52 MBM procedures with 180 resections were performed in 43 patients. The complete endoscopic resection was achieved in 92.3% (95% confidence interval [CI] 81.8-96.9%). The sizes of the lesions ranged from 10 × 8 mm to 25 × 23 mm. The mean operation time is 37 ± 5 min. The operative acute bleeding complication was 7.6% (95% CI 3-18.1%); no perforations occurred. Early complications consisted of delayed bleeding (one patient 1.9%; 95% CI 0.3-10.1%) and slight esophageal stenosis (one patient). The histopathological diagnosis of 26 cases (51%) was consistent between biopsy and MBM samples, while 20 lesions exhibited higher grade dysplasia. The local recurrence rate was 6.9% (3/43) at 1 year, 9.3% (4/43) at 2 years, and 9.3% at 2.5 years. No death occurred during follow-up. CONCLUSIONS: MBM is a safe and effective technique for the treatment of early esophageal cancer and precancerous lesions.

Efficient total synthesis and biological activities of 6-deoxyisojacareubin.

6-Deoxyisojacareubin was directly synthesized in a six-step route with an overall yield of about 20%. In this route, the excellent site selectivity of this Claisen rearrangement-cyclization reaction cascade was achieved by inserting a bulky p-tosyl group into the free 1-OH, and in the last step, some efficient demethylation methods were explored. Furthermore, all synthesized intermediates including 6-deoxyisojacareubin were evaluated for their inhibitory activity against the QGY-7703 cell line. Of these, compound 1 and 6-deoxyisojacareubin showed moderate activities with IC50 values of 39.61 and 9.65 µM, respectively, when compared to the positive control 5-fluorouracil with an IC50 value of 11.24 µM. Further investigation using non-radioactive detection of protein kinase C (PKC) suggested that these two compounds possessed potency in the inhibition of PKC.

Genetic association of hypertension and several other metabolic disorders with Bell's palsy.

Background: Effects of hypertension, type 2 diabetes and obesity on Bell's palsy risk remains unclear. The aim of the study was to explore whether hypertension and these metabolic disorders promoted Bell's palsy at the genetic level. Methods: Genetic variants from genome-wide association studies for hypertension, type 2 diabetes, body mass index and several lipid metabolites were adopted as instrumental variables. Two-sample Mendelian randomization including IVW and MR-Egger was used to measure the genetic relationship between the exposures and Bell's palsy. Sensitivity analyses (i.e., Cochran's Q test, MR-Egger intercept test, "leave-one-SNP-out" analysis and funnel plot) were carried out to assess heterogeneity and horizontal pleiotropy. All statistical analyses were performed using R software. Results: Hypertension was significantly associated with the increased risk of Bell's palsy (IVW: OR = 2.291, 95%CI = 1.025-5.122, p = 0.043; MR-Egger: OR = 16.445, 95%CI = 1.377-196.414, p = 0.029). Increased level of LDL cholesterol might upexpectedly decrease the risk of the disease (IVW: OR = 0.805, 95%CI = 0.649-0.998, p = 0.048; MR-Egger: OR = 0.784, 95%CI = 0.573-1.074, p = 0.132). In addition, type 2 diabetes, body mass index and other lipid metabolites were not related to the risk of Bell's palsy. No heterogeneity and horizontal pleiotropy had been found. Conclusion: Hypertension might be a risk factor for Bell's palsy at the genetic level, and LDL cholesterol might reduce the risk of the disease. These findings (especially for LDL cholesterol) need to be validated by further studies.

Suppression of top-down influence decreases both behavioral and V1 neuronal response sensitivity to stimulus orientations in cats.

How top-down influence affects behavioral detection of visual signals and neuronal response sensitivity in the primary visual cortex (V1) remains poorly understood. This study examined both behavioral performance in stimulus orientation identification and neuronal response sensitivity to stimulus orientations in the V1 of cat before and after top-down influence of area 7 (A7) was modulated by non-invasive transcranial direct current stimulation (tDCS). Our results showed that cathode (c) but not sham (s) tDCS in A7 significantly increased the behavioral threshold in identifying stimulus orientation difference, which effect recovered after the tDCS effect vanished. Consistently, c-tDCS but not s-tDCS in A7 significantly decreased the response selectivity bias of V1 neurons for stimulus orientations, which effect could recover after withdrawal of the tDCS effect. Further analysis showed that c-tDCS induced reduction of V1 neurons in response selectivity was not resulted from alterations of neuronal preferred orientation, nor of spontaneous activity. Instead, c-tDCS in A7 significantly lowered the visually-evoked response, especially the maximum response of V1 neurons, which caused a decrease in response selectivity and signal-to-noise ratio. By contrast, s-tDCS exerted no significant effect on the responses of V1 neurons. These results indicate that top-down influence of A7 may enhance behavioral identification of stimulus orientations by increasing neuronal visually-evoked response and response selectivity in the V1.

Astragaloside IV derivative HHQ16 ameliorates infarction-induced hypertrophy and heart failure through degradation of lncRNA4012/9456.

Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.