Link prediction in protein-protein interaction network: A similarity multiplied similarity algorithm with paths of length three.

Protein-protein interactions (PPIs) are crucial for various biological processes, and predicting PPIs is a major challenge. To solve this issue, the most common method is link prediction. Currently, the link prediction methods based on network Paths of Length Three (L3) have been proven to be highly effective. In this paper, we propose a novel link prediction algorithm, named SMS, which is based on L3 and protein similarities. We first design a mixed similarity that combines the topological structure and attribute features of nodes. Then, we compute the predicted value by summing the product of all similarities along the L3. Furthermore, we propose the Max Similarity Multiplied Similarity (maxSMS) algorithm from the perspective of maximum impact. Our computational prediction results show that on six datasets, including S. cerevisiae, H. sapiens, and others, the maxSMS algorithm improves the precision of the top 500, area under the precision-recall curve, and normalized discounted cumulative gain by an average of 26.99%, 53.67%, and 6.7%, respectively, compared to other optimal methods.

Dose-response relationships between body-mass index and pressure injuries occurrence in hospitalized patients: A multi-center prospective study.

BACKGROUND: Pressure injuries (PIs) are one of the leading potentially preventable hospital-acquired complications associated with prolonged hospital length, poor quality of life and financial burden. The relationship between body mass index (BMI) and PIs occurrence is controversial. OBJECTIVE: The aim of this study was to further examine relationships between BMI and PIs occurrence in hospitalized patients. DESIGN: A multi-center prospective study. SETTING: 39 hospitals located in northwest China from April 2021 to July 2023. PARTICIPANTS: 175,960 hospitalized patients aged over 18 years were enrolled, and 170,800 patients were included in the final analysis. METHODS: BMI and clinical characteristics were assessed at baseline. PIs assessment were performed by trained nurses, with data recorded for the presence, the location and stage of each PI. For staging PIs, the National Pressure Ulcer Advisory Panel（NPUAP） staging system were used. The multivariate logistic regressions analysis and restricted cubic splines (RCS) models were used to explore associations between BMI and PIs, adjusting for potential confounders. RESULTS: Of 175,960 participants, 5160 were excluded from analyses. The multivariate logistic regression model identified a positive relationship between under-weight BMI and risk of PIs occurrence (OR = 1.60, 95% CI:1.18-2.17). We also found U shaped association between BMI and PIs occurrence (non-linear P < 0.001). BMI less than 23 kg/m2 significantly increased risk of PIs, and there was a tendency to increase risk of PIs at BMI higher than 30 kg/m2. We stratified participants by sex to further investigate their association and found the risk of PIs increases substantially in women at BMI below 17 kg/m2 and in men at BMI below 23 kg/m2. CONCLUSIONS: The present study indicated that there was an approximate U shaped relationship between BMI and PIs occurrence, and this association was potentially different between men and women.

Triplane technique for breast reconstruction after breast cancer surgery: A case series report.

RATIONALE: Implant-based breast reconstruction is an important method for post-mastectomy breast reconstruction. Currently, the most commonly used technique is the biplane technique. However, the high rate of postoperative complications, the inability of pockets to accommodate larger implants, and the expensive costs of biological mesh make the development of new surgical methods urgent. The triplane technique for breast reconstruction is an ideal candidate method. PATIENT CONCERNS: The main local symptoms were breast lump, abnormal breast skin, nipple discharge, and abnormal nipple or areola in 24 patients. DIAGNOSES: The study included 24 female patients who underwent breast reconstruction using the triplane technique after radical breast cancer surgery. INTERVENTIONS: The surgical procedure involved measuring the dimensions of the breast, designing the incision, and creating a pocket for the implant using the triplane technique, which includes the pectoralis major muscle, the pectoralis major fascia continuing to the rectus abdominis fascia, and the latissimus dorsa muscle fascia continuing to the rectus abdominis fascia. Postoperative follow-up included regular assessments of pain and evaluation of breast appearance. OUTCOMES: No cases of postoperative infection were observed in all patients. During the 1-year follow-up period after surgery, 5 patients (20.8%) who needed radiotherapy after mastectomy for cancer showed slight darkening of skin flap pigment after using the triplane technique implant. No cases of exposure or infection of the expanders were reported, and 1 patient underwent expander replacement with a permanent prosthesis. All patients expressed satisfaction with the reconstructed breast shape. The 10 patients (41.7%) experiencing postoperative swelling and pain. However, the pain gradually subsided during the postoperative recovery period. No cases of local recurrence or distant metastasis of breast cancer were observed during the 1-year-follow-up period. LESSONS: The triplane technique for breast reconstruction after breast cancer surgery provides good implant coverage, reduces the risk of complications, and is cost-effective.

Fabrication of Interface Engineered S-Scheme Heterojunction Nanocatalyst for Ultrasound-Triggered Sustainable Cancer Therapy.

In order to establish a set of perfect heterojunction designs and characterization schemes, step-scheme (S-scheme) BiOBr@Bi2S3 nanoheterojunctions that enable the charge separation and expand the scope of catalytic reactions, aiming to promote the development and improvement of heterojunction engineering is developed. In this kind of heterojunction system, the Fermi levels mediate the formation of the internal electric field at the interface and guide the recombination of the weak redox carriers, while the strong redox carriers are retained. Thus, these high-energy electrons and holes are able to catalyze a variety of substrates in the tumor microenvironment, such as the reduction of oxygen and carbon dioxide to superoxide radicals and carbon monoxide (CO), and the oxidation of H2O to hydroxyl radicals, thus achieving sonodynamic therapy and CO combined therapy. Mechanistically, the generated reactive oxygen species and CO damage DNA and inhibit cancer cell energy levels, respectively, to synergistically induce tumor cell apoptosis. This study provides new insights into the realization of high efficiency and low toxicity in catalytic therapy from a unique perspective of materials design. It is anticipated that this catalytic therapeutic method will garner significant interest in the sonocatalytic nanomedicine field.

Defect-Repaired g-C3N4 Nanosheets: Elevating the Efficacy of Sonodynamic Cancer Therapy Through Enhanced Charge Carrier Migration.

Sonodynamic therapy (SDT) has garnered growing interest owing to its high tissue penetration depth and minimal side effects. However, the lack of efficient sonosensitizers remains the primary limiting factor for the clinical application of this treatment method. Here, defect-repaired graphene phase carbon nitride (g-C3N4) nanosheets are prepared and utilized for enhanced SDT in anti-tumor treatment. After defect engineering optimization, the bulk defects of g-C3N4 are significantly reduced, resulting in higher crystallinity and exhibiting a polyheptazine imide (PHI) structure. Due to the more extended conjugated structure of PHI, facilitating faster charge transfer on the surface, it exhibits superior SDT performance for inducing apoptosis in tumor cells. This work focuses on introducing a novel carbon nitride nanomaterial as a sonosensitizer and a strategy for optimizing sonosensitizer performance by reducing bulk defects.

Comparative Transcriptome Analysis Provides Insights into the Effect of Epicuticular Wax Accumulation on Salt Stress in Coconuts.

The coconut is an important tropical economical crop and exhibits high tolerance to various types of salinity stress. However, little is known about the molecular mechanism underlying its salt tolerance. In this study, RNA-Seq was applied to examine the different genes expressed in four coconut varieties when exposed to a salt environment, resulting in the generation of data for 48 transcriptomes. Comparative transcriptome analysis showed that some genes involved in cutin and wax biosynthesis were significantly upregulated in salt treatment compared to the control, including CYP86A4, HTH, CER1, CER2, CER3, DCR, GPAT4, LTP3, LTP4, and LTP5. In particular, the expression of CER2 was induced more than sixfold, with an RPKM value of up to 205 ten days after salt treatment in Hainan Tall coconut, demonstrating superior capacity in salt tolerance compared to dwarf coconut varieties. However, for yellow dwarf and red dwarf coconut varieties, the expression level of the CER2 gene was low at four different time points after exposure to salt treatment, suggesting that this gene may contribute to the divergence in salt tolerance between tall and dwarf coconut varieties. Cytological evidence showed a higher abundance of cuticle accumulation in tall coconut and severe damage to cuticular wax in dwarf coconut.

Therapeutic potential of a synthetic dual JAK1/TYK2 inhibitor in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and incurable disease with an increasing incidence rate and low mortality rate. Selectively inhibiting JAK1 and TYK2 has been proposed as a strategy to enhance the efficacy of such inhibitors while minimizing the potential side effects on other JAK isoforms. Our previous studies identified small molecule 18 as a JAK1/TYK2 inhibitor with high selectivity and a new structure. Specifically, the IC50 of 18 at the kinase level reached 39 nM and 21 nM for JAK1 and TYK2, respectively, with 10-fold selectivity over both JAK2 and JAK3. In in vitro studies, 18 dose-dependently inhibited cytokine-induced STAT phosphorylation downstream of the JAK1 and TYK2 signaling pathway. In pharmacokinetic experiments, 18 demonstrated an oral bioavailability of 59.82%, making it a promising candidate for further in vivo studies. Using two mouse models of acute ulcerative colitis (UC) induced by the administration of dextran sulfate sodium (DSS) or oxazolone (OXA), 18 dose-dependently showed a better therapeutic effect than the positive control drug tofacitinib. Additionally, after long-term administration for 32 days, 18 displayed low toxicity to mice and a high safety profile. Taken together, these findings suggest that 18 is a JAK1/TYK2 dual inhibitor with therapeutic effects superior to those of tofacitinib in the treatment of IBD. Moreover, 18 is also a suitable clinical candidate for further investigation in diseases with strong involvement from interferon and/or IL-12/IL-23 in their pathogenesis. This study confirmed the therapeutic effect and long-term safety of inhibiting JAK1 and TYK2 to treat IBD.

Metabolome profiling and transcriptome analysis filling the early crucial missing steps of piperine biosynthesis in Piper nigrum L.

Black pepper (Piper nigrum L.), the world renown as the King of Spices, is not only a flavorsome spice but also a traditional herb. Piperine, a species-specific piper amide, is responsible for the major bioactivity and pungent flavor of black pepper. However, several key steps for the biosynthesis of piperoyl-CoA (acyl-donor) and piperidine (acyl-acceptor), two direct precursors for piperine, remain unknown. In this study, we used guilt-by-association analysis of the combined metabolome and transcriptome, to identify two feruloyldiketide-CoA synthases responsible for the production of the C5 side chain scaffold feruloyldiketide-CoA intermediate, which is considered the first and important step to branch metabolic fluxes from phenylpropanoid pathway to piperine biosynthesis. In addition, we also identified the first two key enzymes for piperidine biosynthesis derived from lysine in P. nigrum, namely a lysine decarboxylase and a copper amine oxidase. These enzymes catalyze the production of cadaverine and 1-piperideine, the precursors of piperidine. In vivo and in vitro experiments verified the catalytic capability of them. In conclusion, our findings revealed enigmatic key steps of piperine biosynthetic pathway and thus provide a powerful reference for dissecting the biosynthetic logic of other piper amides.

Impact of income inequality on carbon emissions: a matter of corruption governance.

Corruption is often linked with income inequality and its impact on carbon emissions. This study investigates the moderating effect of corruption governance on the relationship between income inequality and carbon emissions. Panel data for 62 countries from 2012 to 2020 were used. We employed a threshold panel regression approach, considering income inequality as the explanatory variable and carbon dioxide emissions as the dependent variable, with corruption governance as the threshold variable. Our findings suggest that enhancing the level of corruption governance can mitigate the CO2 emissions driven by income inequality. Specifically, we found a shift in the impact on CO2 emissions when corruption governance crosses a certain threshold. This study provides insights into how improving corruption governance can help in managing the environmental effects of income inequality.

Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers.

Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a Kd value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.

Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies.

Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.

The potential role of ferroptosis in the physiopathology of deep tissue injuries.

Deep tissue injuries (DTIs) are a serious type of pressure injuries that mainly occur at the bony prominences and can develop rapidly, making prevention and treatment more difficult. Although consistent research efforts have been made over the years, the cellular and molecular mechanisms contributing to the development of DTIs remain unclear. More recently, ferroptosis, a novel regulatory cell death (RCD) type, has been identified that is morphological, biochemical and genetic criteria distinct from apoptosis, autophagy and other known cell death pathways. Ferroptosis is characterized by iron overload, iron-dependent lipid peroxidation and shrunken mitochondria. We also note that some of the pathological features of DTI are known to be key features of the ferroptosis pathway. Numerous studies have confirmed that ferroptosis may be involved in chronic wounds, including DTIs. Here, we elaborate on the basic pathological features of ferroptosis. We also present the evidence that ferroptosis is involved in the pathology of DTIs and highlight a future perspective on this emerging field, desiring to provide more possibilities for the prevention and treatment of DTIs.

Advanced hormone receptor-positive/human epidermal growth factor receptor 2-positive invasive ductal carcinoma with cecal metastasis: A case report.

The incidence of gastrointestinal metastases from breast cancer (BC) is low. We report a special case of Luminal B (Hormone Receptor positive [HR+]/Human Epidermal Growth Factor receptor 2-positive [HER-2+]) BC. The patient presented with asymptomatic brain metastases two years after radical surgery for modified breast cancer and developed right lower abdominal pain during relief therapy. Electronic gastroenteroscopy revealed inflammatory changes in the cecal mucosa. These changes were confirmed on pathology to be cecal metastasis from BC. The patient's condition was stabilised after treatment with an antibody-drug conjugate (ADC). For patients with BC who develop appendicitis-like symptoms after treatment for invasive ductal carcinoma of the breast, clinicians should be fully aware that the possibility of cecal metastasis needs to be considered, despite the very low probability of occurrence.

Cutting-Force Modeling Study on Vibration-Assisted Micro-Milling of Bone Materials.

This study aims to enhance surgical safety and facilitate patient recovery through the investigation of vibration-assisted micro-milling technology for bone-material removal. The primary objective is to reduce cutting force and improve surface quality. Initially, a predictive model is developed to estimate the cutting force during two-dimensional (2D) vibration-assisted micro-milling of bone material. This model takes into account the anisotropic structural characteristics of bone material and the kinematics of the milling tool. Subsequently, an experimental platform is established to validate the accuracy of the cutting-force model for bone material. Micro-milling experiments are conducted on bone materials, with variations in cutting direction, amplitude, and frequency, to assess their impact on cutting force. The experimental results demonstrate that selecting appropriate machining parameters can effectively minimize cutting force in 2D vibration-assisted micro-milling of bone materials. The insights gained from this study provide valuable guidance for determining cutting parameters in vibration-assisted micro-milling of bone materials.

Photoredox-catalyzed diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indole derivatives.

Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland-Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.

Painless Stochastic Conjugate Gradient for Large-Scale Machine Learning.

Conjugate gradient (CG), as an effective technique to speed up gradient descent algorithms, has shown great potential and has widely been used for large-scale machine-learning problems. However, CG and its variants have not been devised for the stochastic setting, which makes them extremely unstable, and even leads to divergence when using noisy gradients. This article develops a novel class of stable stochastic CG (SCG) algorithms with a faster convergence rate via the variance-reduced technique and an adaptive step size rule in the mini-batch setting. Actually, replacing the use of a line search in the CG-type approaches which is time-consuming, or even fails for SCG, this article considers using the random stabilized Barzilai-Borwein (RSBB) method to obtain an online step size. We rigorously analyze the convergence properties of the proposed algorithms and show that the proposed algorithms attain a linear convergence rate for both the strongly convex and nonconvex settings. Also, we show that the total complexity of the proposed algorithms matches that of modern stochastic optimization algorithms under different cases. Scores of numerical experiments on machine-learning problems demonstrate that the proposed algorithms outperform state-of-the-art stochastic optimization algorithms.

Defect Engineering in Biomedical Sciences.

With the promotion of nanochemistry research, large numbers of nanomaterials have been applied in vivo to produce desirable cytotoxic substances in response to endogenous or exogenous stimuli for achieving disease-specific therapy. However, the performance of nanomaterials is a critical issue that is difficult to improve and optimize under biological conditions. Defect-engineered nanoparticles have become the most researched hot materials in biomedical applications recently due to their excellent physicochemical properties, such as optical properties and redox reaction capabilities. Importantly, the properties of nanomaterials can be easily adjusted by regulating the type and concentration of defects in the nanoparticles without requiring other complex designs. Therefore, this tutorial review focuses on biomedical defect engineering and briefly discusses defect classification, introduction strategies, and characterization techniques. Several representative defective nanomaterials are especially discussed in order to reveal the relationship between defects and properties. A series of disease treatment strategies based on defective engineered nanomaterials are summarized. By summarizing the design and application of defective engineered nanomaterials, a simple but effective methodology is provided for researchers to design and improve the therapeutic effects of nanomaterial-based therapeutic platforms from a materials science perspective.

The Host Protein CAD Regulates the Replication of FMDV through the Function of Pyrimidines' De Novo Synthesis.

Foot-and-mouth disease virus (FMDV) is a single-stranded picornavirus that causes economically devastating disease in even-hooved animals. There has been little research on the function of host cells during FMDV infection. We aimed to shed light on key host factors associated with FMDV replication during acute infection. We found that HDAC1 overexpression in host cells induced upregulation of FMDV RNA and protein levels. Activation of the AKT-mammalian target of rapamycin (mTOR) signaling pathway using bpV(HOpic) or SC79 also promoted FMDV replication. Furthermore, short hairpin RNA (shRNA)-induced suppression of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), a transcription factor downstream of the AKT-mTOR signaling pathway, resulted in downregulation of FMDV RNA and protein levels. Coimmunoprecipitation assays showed that the ACTase domain of CAD could interact with the FMDV 2C protein, suggesting that the ACTase domain of CAD may be critical in FMDV replication. CAD proteins participate in de novo pyrimidine synthesis. Inhibition of FMDV replication by deletion of the ACTase domain of CAD in host cells could be reversed by supplementation with uracil. These results revealed that the contribution of the CAD ACTase domain to FMDV replication is dependent on de novo pyrimidine synthesis. Our research shows that HDAC1 promotes FMDV replication by regulating de novo pyrimidine synthesis from CAD via the AKT-mTOR signaling pathway. IMPORTANCE Foot-and-mouth disease virus is an animal virus of the Picornaviridae family that seriously harms the development of animal husbandry and foreign trade of related products, and there is still a lack of effective means to control its harm. Replication complexes would generate during FMDV replication to ensure efficient replication cycles. 2C is a common viral protein in the replication complex of Picornaviridae virus, which is thought to be an essential component of membrane rearrangement and viral replication complex formation. The host protein CAD is a key protein in the pyrimidines de novo synthesis. In our research, the interaction of CAD and FMDV 2C was demonstrated in FMDV-infected BHK-21 cells, and it colocalized with 2C in the replication complex. The inhibition of the expression of FMDV 3D protein through interference with CAD and supplementation with exogenous pyrimidines reversed this inhibition, suggesting that FMDV might recruit CAD through the 2C protein to ensure pyrimidine supply during replication. In addition, we also found that FMDV infection decreased the expression of the host protein HDAC1 and ultimately inhibited CAD activity through the AKT-mTOR signaling pathway. These results revealed a unique means of counteracting the virus in BHK-21 cells lacking the interferon (IFN) signaling pathway. In conclusion, our study provides some potential targets for the development of drugs against FMDV.

UPLC-MS/MS method development and application to pharmacokinetic study in rats and dogs of Flonoltinib Maleat.

Flonoltinib Maleate (FM) is a novel selective inhibitor of Janus kinase 2/FMS-like tyrosine kinase 3 (JAK2/FLT3). In this study, we developed an ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure the plasma concentrations of FM in rats and dogs for pharmacokinetic studies. For chromatographic separation, we used a BEH C18 column (2.1 × 50 mm, 1.7 µm particle size) in HPLC. The mobile phase A consisted of a water solution containing 0.1% formic acid (FA) and 2 mM NH4OAc, mixed with acetonitrile (ACN) (V:V = 95:5). The mobile phase B was a water solution containing 0.1% FA and 2 mM NH4OAc, mixed with ACN (V:V = 5:95), which was used for gradient elution. We used multiple reactive ion detection (MRM) mode and electrospray ionization positive (ESI+) mode for quantitative analysis. The standard curve was linear in the concentration range of 0.5 to 500 ng/ml in rat and dog plasma. The intra-batch and inter-batch precision (RSD%) of FM in rat and dog plasma was less than 15%. The intra-batch and inter-batch accuracy was 88.3-106.5% and 92.0-100.6% in rats, and 94.7-106.6% and 95.3-103.8% in dogs, respectively. The RSD (%) of matrix factors (MF) normalized to the internal standard (IS) of FM in rat and dog plasma was ≤5.6% and ≤3.0%, respectively. The extraction recovery and carryover were considered acceptable. When the sample concentration was higher than the upper limit of quantitation (ULOQ), the 10-fold dilution was reliable within the limits of acceptability. The UPLC-MS/MS method developed in this study was successfully applied in measuring the pharmacokinetic parameters of FM in rats and dogs after intravenous and oral administration, laying a foundation for the preclinical pharmacokinetic study of FM and providing a reference for clinical pharmacokinetic studies.

Rational design and appraisal of selective Cdc2-Like kinase 1 (Clk1) inhibitors as novel autophagy inducers for the treatment of acute liver injury (ALI).

Autophagy inducers are promising agents for treating certain medical illnesses, while no safe autophagy inducers are in clinical applications. Cdc2-like kinase 1 (Clk1) inhibitors induce autophagy efficiently; however, most Clk1 inhibitors lack selectivity, especially against Dyrk1A kinase. Herein, we report a series of 1H-pyrrolo[2,3-b]pyridin-5-amine derivatives as novel Clk1 inhibitors. Through detailed structural modification and structure-activity relationship studies, compound 10ad shows potent and selective inhibition for Clk1, with an IC50 value of 5 nM and over 300-fold selectivity for Dyrk1A. Related kinase screening also validates the selectivity of compound 10ad. Furthermore, compound 10ad potently induces autophagy in vitro and exhibits significant hepatoprotective effects in the acute liver injury model induced by acetaminophen (paracetamol). In general, due to the excellent potency and selectivity, compound 10ad was worth further investigation in the treatment of autophagy-related diseases.