TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes.

Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P(2) and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na(+), not K(+), as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P(2) in regulating the fusogenic potential of intracellular organelles.

Regulation of PKR-dependent RNA translation inhibition by TRIM21 upon virus infection or other stress.

The host always employs various ways to defend against viral infection and spread. However, viruses have evolved their own effective strategies, such as inhibition of RNA translation of the antiviral effectors, to destroy the host's defense barriers. Protein synthesis, commonly controlled by the α-subunit of eukaryotic translation initiation factor 2 (eIF2α), is a basic cellular biological process among all species. In response to viral infection, in addition to inducing the transcription of antiviral cytokines by innate immunity, infected cells also inhibit the RNA translation of antiviral factors by activating the protein kinase R (PKR)-eIF2α signaling pathway. Regulation of innate immunity has been well studied; however, regulation of the PKR-eIF2α signaling pathway remains unclear. In this study, we found that the E3 ligase TRIM21 negatively regulates the PKR-eIF2α signaling pathway. Mechanistically, TRIM21 interacts with the PKR phosphatase PP1α and promotes K6-linked polyubiquitination of PP1α. Ubiquitinated PP1α augments its interaction with PKR, causing PKR dephosphorylation and subsequent translational inhibition release. Furthermore, TRIM21 can constitutively restrict viral infection by reversing PKR-dependent translational inhibition of various previously known and unknown antiviral factors. Our study highlights a previously undiscovered role of TRIM21 in regulating translation, which will provide new insights into the host antiviral response and novel targets for the treatment of translation-associated diseases in the clinic.

Experimental demonstration on 400†nm-scale bandwidth optical parametric chirped-pulse amplification based on mixed cascaded crystals.

We present an optical parametric chirped-pulse amplification (OPCPA) based on mixed cascaded crystals, taking advantage of the unique parametric phase-matching of lithium triborate (LiB3O5, LBO) and yttrium calcium oxyborate ((YCa4O(BO3)3, YCOB) crystals. The OPCPA properties of LBO at 880 nm and YCOB at 750 nm are studied respectively. After amplification by two LBO and two YCOB crystals, a total signal gain of 108 and spectral bandwidth close to 400 nm is obtained. After accurate dispersion compensation with a grating-pair compressor and chirped mirror compensator, a pulse duration of 9.4 fs is obtained by a SHG-frequency-resolved optical grating (FROG). This approach will be of great significance in high energy amplifier for high peak power few-cycle laser sources.

Assessing public health service capability of primary healthcare personnel: a large-scale survey in Henan Province, China.

BACKGROUND: The public health service capability of primary healthcare personnel directly affects the utilization and delivery of health services, and is influenced by various factors. This study aimed to examine the status, factors, and urban-rural differences of public health service capability among primary healthcare personnel, and provided suggestions for improvement. METHODS: We used cluster sampling to survey 11,925 primary healthcare personnel in 18 regions of Henan Province from 20th to March 31, 2023. Data encompassing demographics and public health service capabilities, including health lifestyle guidance, chronic disease management, health management of special populations, and vaccination services. Multivariable regression analysis was employed to investigate influencing factors. Propensity Score Matching (PSM) quantified urban-rural differences. RESULTS: The total score of public health service capability was 80.17 points. Chronic disease management capability scored the lowest, only 19.60. Gender, education level, average monthly salary, professional title, health status, employment form, work unit type, category of practicing (assistant) physician significantly influenced the public health service capability (all P < 0.05). PSM analysis revealed rural primary healthcare personnel had higher public health service capability scores than urban ones. CONCLUSIONS: The public health service capability of primary healthcare personnel in Henan Province was relatively high, but chronic disease management required improvement. Additionally, implementing effective training methods for different subgroups, and improving the service capability of primary medical and health institutions were positive measures.

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.

Genome-wide identification of the Hsp70 gene family in Penaeus chinensis and their response to environmental stress.

The heat shock protein 70 (HSP70) gene family plays a crucial role in the response of organisms to environmental stress. However, it has not been systematically characterized in shrimp. In this study, we identified 25 PcHsp70 genes in the Penaeus chinensis genome. The encoded proteins were categorized into six subgroups based on phylogenetic relationships. Tandem duplication was the main driver of amplification in the PcHsp70 family, and the genes have experienced strong purifying selection during evolution. Transcriptome data analysis revealed that the 25 PcHsp70 members have different expression patterns in shrimp under conditions of low temperature, low salinity, and white spot syndrome virus infection. Among them, PcHsp70.11 was significantly induced under all three stress conditions, suggesting that this gene plays an important role in response to environmental stress in P. chinensis. To the best of our knowledge, this is the first study to systematically analyze the Hsp70 gene family in shrimp. The results provide important information on shrimp Hsp70s, contributing to a better understanding of the role of these genes in environmental stress and providing a basis for further functional studies.

Electron-Donating Conjugation Effect Modulated Zn2+ Reduction Reaction for Separator-Free Aqueous Zinc Batteries.

Zinc-based aqueous batteries (ZABs) are attracting extensive attention due to the low cost, high capacity, and environmental benignity of the zinc anode. However, their application is still hindered by the undesired zinc dendrites. Despite Zn-surface modification being promising in relieving dendrites, a thick separator (i.e. glass fiber, 250-700 µm) is still required to resist the dendrite puncture, which limits volumetric energy density of battery. Here, we pivot from the traditional interphase plus extra separator categories, proposing an all-in-one ligand buffer layer (ca. 20 µm) to effectively modulate the Zn2+ transfer and deposition behaviors proved by in situ electrochemical digital holography. Experimental characterizations and density functional theory simulations further reveal that the catechol groups in the buffer layer can accelerate the Zn2+ reduction reaction (ZRR) through the electron-donating p-π conjugation effect, decreasing the negative charge in the coordination environment. Without extra separators, the elaborated system endows low polarization below 28.2 mV, long lifespan of 4950 h at 5 mA cm-2 in symmetric batteries, and an unprecedented volumetric energy density of 99.2 Wh L-1 based on the whole pouch cells. The concomitantly "separator-free" and "dendrite-free" conjugation effect with an accelerated ZRR process could foster the progression of metallic anodes and benefit energetic aqueous batteries.

High-Energy Sn-Ni and Sn-Air Aqueous Batteries via Stannite-Ion Electrochemistry.

Tin is promising for aqueous batteries (ABs) due to its multiple electrons' reactions, high corrosion resistance, large hydrogen overpotential, and excellent environmental compatibility. However, restricted to the high thermodynamic barrier and the poor electrochemical kinetics, efficient alkaline Sn plating/stripping at facile conditions has not yet been realized. Here, for the first time, we demonstrate a highly reversible stannite-ion electrochemistry and construct a novel paradigm of high-energy Sn-based ABs. Combined spectroscopic characterization, electrochemical evaluation, and theoretical computation reveal the thermodynamic merits with a low reaction energy barrier and feasible H2O participation in Sn-ion reduction as well as the kinetic merits with fastened surface charge transfer and SnO22- diffusion. The resultant alkaline Sn anode delivers a low potential of -1.07 V vs Hg/HgO, a specific capacity of 450 mA h g-1, a Coulombic efficiency of near 100%, superb rate capability at 45.5 A g-1, and excellent cycling durability without dendrite and dead Sn. As a proof of concept, we developed new high-energy Sn-based ABs, including 1.45 V Sn-Ni with 314 W h kg-1 (58 kW kg-1 and over 15,000 cycles) and 1.0 V Sn-air with 420 W h kg-1 (lifespan over 1900 h), on the basis of masses from cathode and anode active materials. The findings prove the feasibility of the alkaline Sn metal anode, and the new suite of high-energy Sn-based ABs may be of immediate benefit toward safe, reliable, and affordable energy storage.

High Throughput and Noninvasive Exosomal PD-L1 Detection for Accurate Immunotherapy Response Prediction via Tim4-Functionalized Magnetic Core-Shell Metal-Organic Frameworks.

Exosomal PD-L1 has been increasingly considered a noninvasive and accurate predictive marker for immunotherapy treatment response. However, the clinical monitoring of exosomal PD-L1 expression is still limited by its complex biological environment as well as the lack of a robust isolation strategy. Here, a Tim4-functionalized magnetic core-shell metal-organic framework (denoted as Fe3O4@SiO2-ILI-01@Tim4) was facilely constructed via layer-by-layer assembly. Owing to the strongly hydrophilic organic ligand of 1,3-bis(4-carboxybutyl)imidazolium bromide (ILI), magnetic Fe3O4@SiO2-ILI-01@Tim4 was endowed with the merits of low nonspecific adsorption and quick, easy, and convenient isolation of exosomes. The capture efficiency of Fe3O4@SiO2-ILI-01@Tim4 reached as high as 90.3 ± 0.5% and the recovery rate for exosomes was up to 93.0 ± 6.1%. The purity of the isolated exosomes was 7.5 times higher than that via the ultracentrifugation (UC) method. By further combination with immunofluorescence assay, high throughput and noninvasive exosomal PD-L1 detection for accurate immunotherapy response prediction was achieved. The prognosis accuracy of the developed Fe3O4@SiO2-ILI-01@Tim4-based strategy reached 85.7%, whereas the prognosis accuracy of the clinical gold standard, the PD-L1 combined positive score (CPS) test, was only 57.1%. Most interestingly, the developed method is especially suitable for those patients receiving false negative results in the CPS test. The proposed Fe3O4@SiO2-ILI-01@Tim4 is a highly efficient and robust technique showing great potential in high throughput and noninvasive exosomal PD-L1 detection for accurately predicting immunotherapy efficacy.

Synthesis of Conductive MOFs and Their Electrochemical Application.

Conductive metal-organic frameworks (MOFs) are a type of porous material. It consists of metal ions coordinated with highly conjugated organic ligands. The high density of carriers and orbital overlap contribute to the amazing conductivity. Additionally, conductive MOFs inherit the advantages of large specific surface area, structural diversity, and adjustable pore size from MOFs. These excellent properties have attracted many researchers to explore controllable synthesis and electrochemical applications over the past decade. This work provides an overview of the recent advances in the synthesis strategies of conductive MOFs and highlights their applications in electrocatalysis, supercapacitors, sensors, and batteries. Finally, the challenges faced by the synthesis and application of conductive MOFs are discussed, as well as the views on promising solutions for them are presented.

Heat Shock-Binding Protein 21 Regulates the Innate Immune Response to Viral Infection.

The induction of interferons (IFNs) plays an important role in the elimination of invading pathogens. Heat shock binding protein 21 (HBP21), first known as a molecular chaperone of HSP70, is involved in tumor development. Heat shock binding proteins have been shown to regulate diverse biological processes, such as cell cycle, kinetochore localization, transcription, and cilium formation. Their role in antimicrobial immunity remains unknown. Here, we found that HBP21 drives a positive feedback loop to promote IRF3-mediated IFN production triggered by viral infection. HBP21 deficiency significantly impaired the virus-induced production of IFN and resulted in greater susceptibility to viral infection both in vitro and in vivo. Mechanistically, HBP21 interacted with IRF3 and promoted the formation of a TBK1-IRF3 complex. Moreover, HBP21 abolished the interaction between PP2A and IRF3 to repress the dephosphorylation of IRF3. Analysis of HBP21 protein structure further confirmed that HBP21 promotes the activation of IRF3 by depressing the dephosphorylation of IRF3 by PP2A. Further study demonstrated that virus-induced phosphorylation of Ser85 and Ser153 of HBP21 itself is important for the phosphorylation and dimerization of IRF3. Our study identifies HBP21 as a new positive regulator of innate antiviral response, which adds novel insight into activation of IRF3 controlled by multiple networks that specify behavior of tumors and immunity. IMPORTANCE The innate immune system is the first-line host defense against microbial pathogen invasion. The physiological functions of molecular chaperones, involving cell differentiation, migration, proliferation and inflammation, have been intensively studied. HBP21 as a molecular chaperone is critical for tumor development. Tumor is related to immunity. Whether HBP21 regulates immunity remains unknown. Here, we found that HBP21 promotes innate immunity response by dual regulation of IRF3. HBP21 interacts with IRF3 and promotes the formation of a TBK1-IRF3 complex. Moreover, HBP21 disturbs the interaction between PP2A and IRF3 to depress the dephosphorylation of IRF3. Analysis of HBP21 protein structure confirms that HBP21 promotes the activation of IRF3 by blocking the dephosphorylation of IRF3 by PP2A. Interestingly, virus-induced Ser85 and Ser153 phosphorylation of HBP21 is important for IRF3 activation. Our findings add to the known novel immunological functions of molecular chaperones and provide new insights into the regulation of innate immunity.

The Role of REC8 in the Innate Immune Response to Viral Infection.

REC8 meiotic recombination protein (REC8) is a member of structural maintenance of chromosome (SMC) protein partners, which play an important role in meiosis, antitumor activity, and sperm formation. As the adaptor proteins of RIG-I-like receptor (RLR) signaling and cyclic GMP-AMP synthase (cGAS)-DNA signaling, the activity and stability of MAVS (mitochondrial antiviral signaling protein; also known as VISA, Cardif, and IPS-1) and STING (stimulator of interferon genes; also known as MITA) are critical for innate immunity. Here, we report that REC8 interacts with MAVS and STING and inhibits their ubiquitination and subsequent degradation, thereby promoting innate antiviral signaling. REC8 is upregulated through the JAK-STAT signaling pathway during viral infection. Knockdown of REC8 impairs the innate immune responses against vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and herpes simplex virus (HSV). Mechanistically, during infection with viruses, the SUMOylated REC8 is transferred from the nucleus to the cytoplasm and then interacts with MAVS and STING to inhibit their K48-linked ubiquitination triggered by RNF5. Moreover, REC8 promotes the recruitment of TBK1 to MAVS and STING. Thus, REC8 functions as a positive modulator of innate immunity. Our work highlights a previously undocumented role of meiosis-associated protein REC8 in regulating innate immunity. IMPORTANCE The innate immune response is crucial for the host to resist the invasion of viruses and other pathogens. STING and MAVS play a critical role in the innate immune response to DNA and RNA viral infection, respectively. In this study, REC8 promoted the innate immune response by targeting STING and MAVS. Notably, REC8 interacts with MAVS and STING in the cytoplasm and inhibits K48-linked ubiquitination of MAVS and STING triggered by RNF5, stabilizing MAVS and STING protein to promote innate immunity and gradually inhibiting viral infection. Our study provides a new insight for the study of antiviral innate immunity.

Sp1 promotes tumour progression by remodelling the mitochondrial network in cervical cancer.

BACKGROUND: Cervical cancer remains one of the most prevalent cancers worldwide. Accumulating evidence suggests that specificity protein 1 (Sp1) plays a pivotal role in tumour progression. The underlying role and mechanism of Sp1 in tumour progression remain unclear. METHODS: The protein level of Sp1 in tumour tissues was determined by immunohistochemistry. The effect of Sp1 expression on the biological characteristics of cervical cancer cells was assessed by colony, wound healing, transwell formation, EdU, and TUNEL assays. Finally, the underlying mechanisms and effects of Sp1 on the mitochondrial network and metabolism of cervical cancer were analysed both in vitro and in vivo. RESULTS: Sp1 expression was upregulated in cervical cancer. Sp1 knockdown suppressed cell proliferation both in vitro and in vivo, while overexpression of Sp1 had the opposite effects. Mechanistically, Sp1 facilitated mitochondrial remodelling by regulating mitofusin 1/2 (Mfn1/2), OPA1 mitochondrial dynamin-like GTPase (Opa1), and dynamin 1-like (Drp1). Additionally, the Sp1-mediated reprogramming of glucose metabolism played a critical role in the progression of cervical cancer cells. CONCLUSIONS: Our study demonstrates that Sp1 plays a vital role in cervical tumorigenesis by regulating the mitochondrial network and reprogramming glucose metabolism. Targeting Sp1 could be an effective strategy for the treatment of cervical cancer.

Titanium Carbide MXene Quantum Dots-Modified Hydroxyapatite Hollow Microspheres as pH/Near-Infrared Dual-Response Drug Carriers.

Titanium carbide MXene quantum dots (MQDs) possess intrinsic regulatory properties and selective toxicity to cancer cells. Here, MDQs were selected for the modification of hydroxyapatite (HA) microspheres, and MXene quantum dots-modified hydroxyapatite (MQDs-HA) hollow microspheres with controllable shapes and sizes were prepared as bone drug carriers. The results show that the prepared MQDs-HA hollow microspheres had a large BET surface area (231.2 m2/g), good fluorescence, and low toxicity. In addition, MQDs-HA showed a mild storage-release behavior and good responsiveness of pH and near-infrared (NIR). Thus, the MQDs-HA hollow microspheres have broad application prospects in the field of drug delivery and photothermal therapy.

Molecular Insights into the Stability of Titanium in Electrolytes Containing Chlorine and Fluorine Ions.

Titanium and its alloys are protected by a compact and stable passive film, which confers resistance to corrosion by the primary halogen chloride (Cl-) while being less effective against fluoride (F-). Although researchers have recognized different macroscopic corrosion effects of these halide ions on titanium, the underlying mechanisms remain largely unexplored. In this work, the bonding of Cl-/F- with stable passive films was studied in neutral and acidic (pH = 2.3) conditions. The synergistic effect between the interfacial hydrogen bond (HB) structure and halogens on titanium corrosion was first revealed using first-principles calculation and Raman spectroscopy. F- forms more stable halogen-Ti bonds than Cl-, resulting in titanium degradation. The proton combined with F- exhibits a specific synergistic effect, causing corrosion of the passive film. The water hydrogen bond transformation index (HBTI) at the titanium/aqueous interface was 1.88 in an acidic solution containing F-, significantly higher than that in neutral/acid solutions containing Cl- (1.80/1.81) and a neutral solution containing F- (1.81). This work clarifies the structure-activity relationship between HBTI and the destruction of titanium passive films. We propose that the microstructure of the interfacial HB is an undeniable factor in the corrosion of titanium.

Transition Metal-Catalyzed Enantioselective Synthesis of Chiral Five- and Six-Membered Benzo O-heterocycles.

Enantiomerically enriched five- and six-membered benzo oxygen heterocycles are privileged architectures in functional organic molecules. Over the last several years, many effective methods have been established to access these compounds. However, comprehensive documents cover updated methodologies still in highly demand. In this review, recent transition metal catalyzed transformations lead to chiral five- and six-membered benzo oxygen heterocycles are presented. The mechanism and chirality transfer or control processes are also discussed in details.

Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney disease.

OBJECTIVE: A ketogenic diet or mildly increased ketone body levels are beneficial for diabetic kidney disease (DKD) patients. Our previous study has found that sodium-coupled monocarboxylate transporter 1 (SMCT1), a key enzyme in charge of ketone reabsorption, possesses beneficial effects on the function of renal tubular epithelial cells (TECs) in energy crisis. Our present study is to investigate whether SMCT1 is important in maintaining the physiological function of renal tubular and plays a role in DKD. METHODS: We tested the expression of SMCT1 in kidney tissues from DKD patients receiving kidney biopsy as well as diabetes mice. We compared the difference of ß-hydroxybutyrate (ß-HB) levels in serum, urine and kidney tissues between diabetic mice and control. Using recombinant adeno-associated viral vector containing SMCT1 (encoded by Slc5a8 gene), we tested the effect of SMCT1 upregulation on microalbuminuria as well as its effects on mitochondrial energy metabolism in diabetic mice. Then we investigated the role of SMCT1 and its ß-HB reabsorption function in maintaining the physiological function of renal tubular using renal tubule-specific Slc5a8 gene knockout mice. Transcriptomes and proteomics analysis were used to explore the underlying mechanism. RESULTS: SMCT1 downregulation was found in DKD patients as well as in diabetic mice. Moreover, diabetic mice had a decreased renal ß-HB level compared with control, and SMCT1 upregulation could improve microalbuminuria and mitochondrial energy metabolism. In renal tubule-specific Slc5a8 gene knockout mice, microalbuminuria occurred early at 24 weeks of age, accompanied by ATP shortage and metabolic reprogramming in the kidney; however, supplementation with ß-HB precursor substance 1,3-butanediol in food alleviated kidney damage as well as energy metabolic reprogramming. CONCLUSIONS: Decreased SMCT1 expression and its ketone reabsorption function play an important role in the occurrence of DKD. SMCT1 may be a new promising target in treating DKD.

Large yellow croaker (Lrimichthys crocea) IL-2 modulates humoral immunity via the conserved JAK-STAT5 signal pathway.

The terminal differentiation of B cells into plasma cells is central to the generation of protective, long-lived humoral immune responses. In mammals, interleukin-2 (IL-2) has been shown to play a role in B cell proliferation and differentiation. However, it remains unclear whether fish IL-2 is involved in B cell proliferation and differentiation. To this end, we investigated the regulatory role of IL-2 in B cell proliferation and differentiation in large yellow croaker (Larimichthys crocea). We found that L. crocea IL-2 (LcIL-2) significantly increased IgM+ B cells proliferation both in vivo and in vitro and facilitated IgM+ B cells differentiation into plasma cells. Furthermore, LcIL-2 increased the production of specific antibodies after immunization with the Vibrio alginolyticus subunit vaccine, recombinant dihydrolipoamide dehydrogenase (rDLD); simultaneous administration of LcIL-2 and rDLD prior to challenge with Vibrio parahaemolyticus or V. alginolyticus significantly increased relative percent survival. Mechanistically, LcIL-2 promoted B cell proliferation and regulated B cell differentiation by triggering the JAK-STAT5 signaling pathway. Collectively, our results demonstrated that LcIL-2 improved B cell proliferation and specific antibody production via the conserved JAK-STAT5 signaling pathway in large yellow croaker, providing valuable insights into the mechanisms underlying the IL-2-mediated regulation of the humoral immune response in fish.

Spontaneous massive fetomaternal hemorrhage: two case reports and a literature review of placental pathology.

BACKGROUND: Massive fetomaternal hemorrhage (FMH) is a rare event during pregnancy that may cause severe fetal anemia or death. CASE PRESENTATION: This paper reports two cases of fetomaternal hemorrhage with unexplained reasons. Both cases required emergency caesarean sections for non-reassuring fetal status and were treated with neonatal blood transfusion. Fetomaternal hemorrhage was confirmed via maternal Kleihauer-Betke test. CONCLUSION: We found parenchymal pallor, increased nucleated red blood cells (nRBCs), and syncytial knots (SKs) in the placentas, which are compatible with fetal anemia. Immunohistochemical staining indicated VEGF, CD34, and CD31 expression in the endothelial cells of the capillaries, characteristic of massive FMH placenta. This article also reviews the particular histopathological changes in FHM placenta according to the placental lesion classification system.

Development of 10-Hydroxycamptothecin-crizotinib conjugate based on the synergistic effect on lung cancer cells.

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.