Application of Asymmetric Catalysis in Chiral Pesticide Active Molecule Synthesis.

The different configurations of chiral pesticides generally have significant influence on their biological activities. Chiral agrochemicals with high optical purities have become a prominent topic in the research field of new pesticides due to their advantages including lower toxicity, higher efficiency, and reduced residue levels. However, most commercially available pesticides that possess chiral elements are still used in their racemic forms. To date, asymmetric catalysis has emerged as a versatile tool for the enantioselective synthesis of various chiral agrochemicals and novel chiral pesticide active molecules. This perspective provides a comprehensive overview of the applications of diverse asymmetric catalytic approaches in the facile preparation of numerous novel pesticide active molecules, and our own outlook on the future development of this highly active research direction is also presented at the end of this review.

Chemodivergent Parallel Kinetic Resolution of Paracyclophanes: Enantiomer Fishing with Different Substrates.

An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N-heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio- and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.

Discovery of novel piperidine-containing thymol derivatives as potent antifungal agents for crop protection.

BACKGROUND: Plant fungal diseases pose a significant threat to crop production. The extensive use of chemical pesticides has led to growing environmental safety risks and pesticide resistance of various plant pathogens. Therefore, it is an urgent task to explore novel eco-friendly fungicidal agents with high efficacy to combat fungal infection. RESULTS: In this study, we rationally designed a series of novel thymol derivatives by incorporation of the sulfonamide moiety and evaluated their biological activities against plant pathogenic fungi. The bioassay results underscored the remarkable in vitro antifungal activity of compounds 5m and 5t against Phytophthora capsici (P. capsici), with EC50 values of 8.420 and 8.414 µg/mL, respectively. Their efficacies were superior to that of widely used commercial fungicides azoxystrobin (AZO, 20.649 µg/mL) and cabendazim (CAB, 251.625 µg/mL). Furthermore, compound 5v exhibited excellent in vitro antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum), with an EC50 value of 12.829 µg/mL, significantly outperforming AZO (63.629 µg/mL). In vivo bioassays demonstrated the impactful activity of compound 5v against S. sclerotiorum, achieving over 98% curative and protective efficacies at the concentration of 200 µg/mL. Further mechanistic investigations unveiled that compound 5v induced mycelial shrinkage and collapse in S. sclerotiorum, resulting in organelle damage and the accumulation of antioxidant enzyme activity. CONCLUSION: The significant antifungal efficacy of the prepared thymol derivatives shall encourage further exploration of compound 5v as a promising candidate to develop novel fungicides for crop protection. © 2024 Society of Chemical Industry.

Synthesis of Planar Chiral Compounds Containing α-Amino Phosphonates for Antiplant Virus Applications against Potato Virus Y.

An unprecedented study of the application of planar chiral compounds in antiviral pesticide development is reported. A class of multifunctional planar chiral ferrocene derivatives bearing α-amino phosphonate moieties was synthesized. These compounds, exhibiting superior optical purities, were subsequently subjected to antiviral evaluations against the notable plant pathogen potato virus Y (PVY). The influence of the absolute configurations of the planar chiral compounds on their antiviral bioactivities was significant. A number of these enantiomerically enriched planar chiral molecules demonstrated superior anti-PVY activities. Specifically, compound (Sp, R)-9n displayed extraordinary curative activities against PVY, with a 50% maximal effective concentration (EC50) of 216.11 µg/mL, surpassing the efficacy of ningnanmycin (NNM, 272.74 µg/mL). The protective activities of compound (Sp, R)-9n had an EC50 value of 152.78 µg/mL, which was better than that of NNM (413.22 µg/mL). The molecular docking and defense enzyme activity tests were carried out using the planar chiral molecules bearing different absolute configurations to investigate the mechanism of their antiviral activities against PVY. (Sp, R)-9n, (Sp, R)-9o, and NMM all showed stronger affinities to the PVY-CP than the (Rp, S)-9n. Investigations into the mechanisms revealed that the planar chiral configurations of the compounds played pivotal roles in the interactions between the PVY-CP molecules and could augment the activities of the defense enzymes. This study contributes substantial insights into the role of planar chirality in defending plants against viral infections.

Access to Axially Chiral Aryl Aldehydes via Carbene-Catalyzed Nitrile Formation and Desymmetrization Reaction.

An approach utilizing N-heterocyclic carbene for nitrile formation and desymmetrization reaction is developed. The process involves kinetic resolution, with the axially chiral aryl monoaldehydes obtained in moderate yields with excellent optical purities. These axially chiral aryl monoaldehydes can be conveniently transformed into functionalized molecules, showing great potential as catalysts in organic chemistry.

Design, synthesis and Anti-PVY activity of planar chiral thiourea derivatives incorporated with [2.2]Paracyclophane.

BACKGROUND: Potato virus Y (PVY) is a prominent representative of plant viruses. It can inflict severe damage upon Solanaceae plants, leading to global dissemination and substantial economic losses. To discover new antiviral agents, a class of planar chiral thiourea molecules through the key step of N-heterocyclic carbene-catalyzed nitrile formation reaction was synthesized with excellent optical purities for antiviral evaluations against plant virus PVY. RESULTS: The absolute configurations of the planar chiral compounds exhibited obvious distinctions in the anti-PVY activities. Notability, compound (S)-4u exhibited remarkable curative activities against PVY, with a half maximal effective concentration (EC50) of 349.3 µg mL-1, which was lower than that of the ningnanmycin (NNM) (EC50 = 400.8 µg mL-1). Additionally, The EC50 value for the protective effects of (S)-4u was 146.2 µg mL-1, which was superior to that of NNM (276.4 µg mL-1). Furthermore, the mechanism-of-action of enantiomers of planar chiral compound 4u was investigated through molecular docking, defensive enzyme activity tests and chlorophyll content tests. CONCLUSION: Biological mechanism studies have demonstrated that the configuration of planar chiral target compounds plays a crucial role in the molecular interaction with PVY-CP, enhancing the activity of defense enzymes and affecting chlorophyll content. The current study has provided significant insights into the roles played by planar chiralities in plant protection against viruses. This paves the way for the development of novel green pesticides bearing planar chiralities with excellent optical purities. © 2024 Society of Chemical Industry.

Design, Synthesis, and Herbicidal Evaluation of Pyrrolidinone-Containing 2-Phenylpyridine Derivatives as Novel Protoporphyrinogen Oxidase Inhibitors.

In this work, a series of pyrrolidinone-containing 2-phenylpyridine derivatives were synthesized and evaluated as novel protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors for herbicide development. At 150 g ai/ha, compounds 4d, 4f, and 4l can inhibit the grassy weeds of Echinochloa crus-galli (EC), Digitaria sanguinalis (DS), and Lolium perenne (LP) with a range of 60 to 90%. Remarkably, at 9.375 g ai/ha, these compounds showed 100% inhibition effects against broadleaf weeds of Amaranthus retroflexus (AR) and Abutilon theophrasti (AT), which were comparable to the performance of the commercial herbicides flumioxazin (FLU) and saflufenacil (SAF) and better than that of acifluorfen (ACI). Molecular docking analyses revealed significant hydrogen bonding and π-π stacking interactions between compounds 4d and 4l with Arg98, Asn67, and Phe392, respectively. Additionally, representative compounds were chosen for in vivo assessment of PPO inhibitory activity, with compounds 4d, 4f, and 4l demonstrating excellent inhibitory effects. Notably, compounds 4d and 4l induced the accumulation of reactive oxygen species (ROS) and a reduction in the chlorophyll (Chl) content. Consequently, compounds 4d, 4f, and 4l are promising lead candidates for the development of novel PPO herbicides.

Discovery of Pyridyl-Benzothiazol Hybrids as Novel Protoporphyrinogen Oxidase Inhibitors via Scaffold Hopping.

In order to discover novel protoporphyrinogen oxidase (PPO) inhibitors with excellent herbicidal activity, a series of structurally novel 6-(pyridin-2-yl) benzothiazole derivatives were designed based on the scaffold hopping strategy. The in vitro experiments demonstrated that the newly synthesized compounds exhibited noteworthy inhibitory activity against Arabidopsis thaliana PPO (AtPPO), with IC50 values ranging from 0.06 to 1.36 µM. Preliminary postemergence herbicidal activity tests and crop safety studies indicated that some of our compounds exhibited excellent herbicidal activity and crop safety. For instance, compound (rac)-7as exhibited superior herbicidal activities to commercially available flumioxazin (FLU) and saflufenacil (SAF) at all the tested concentrations and showed effective herbicidal activities even at a dosage as low as 18.75 g ai/ha. Meanwhile, compound (rac)-7as showed good crop safety for wheat at a dosage as high as 150 g of ai/ha. Although the absolute configuration of compound 7as has no obvious effect on its herbicidal activity, compound (R)-7as showed a slightly higher crop safety than compound (S)-7as. Molecular simulation studies of Nicotiana tabacum PPO (NtPPO) and our candidate compounds showed that the benzothiazole moiety of compounds (R)-7as or (S)-7as formed multiple π-π stacking interactions with FAD, and the pyridine ring generated π-π stacking with Phe-392. Our finding proved that the pyridyl-benzothiazol hybrids are promising scaffolds for the development of PPO-inhibiting herbicides.

The prediction of the survival in patients with severe trauma during prehospital care: Analyses based on NTDB database.

PURPOSE: Traumas cause great casualties, accompanied by heavy economic burdens every year. The study aimed to use ML (machine learning) survival algorithms for predicting the 8-and 24-hour survival of severe traumas. METHODS: A retrospective study using data from National Trauma Data Bank (NTDB) was conducted. Four ML survival algorithms including survival tree (ST), random forest for survival (RFS) and gradient boosting machine (GBM), together with a Cox proportional hazard model (Cox), were utilized to develop the survival prediction models. Following this, model performance was determined by the comparison of the C-index, integrated Brier score (IBS) and calibration curves in the test datasets. RESULTS: A total of 191,240 individuals diagnosed with severe trauma between 2015 and 2018 were identified. Glasgow Coma Scale (GCS), trauma type, age, SaO2, respiratory rate (RR), systolic blood pressure (SBP), EMS transport time, EMS on-scene time, pulse, and EMS response time were identified as the main predictors. For predicting the 8-hour survival with the complete cases, the C-indexes in the test sets were 0.853 (0.845, 0.861), 0.823 (0.812, 0.834), 0.871 (0.862, 0.879) and 0.857 (0.849, 0.865) for Cox, ST, RFS and GBM, respectively. Similar results were observed in the 24-hour survival prediction models. The prediction error curves based on IBS also showed a similar pattern for these models. Additionally, a free web-based calculator was developed for potential clinical use. CONCLUSION: The RFS survival algorithms provide non-parametric alternatives to other regression models to be of clinical use for estimating the survival probability of severe trauma patients.

Discovery of Novel Chiral Indole Derivatives Containing the Oxazoline Moiety as Potential Antiviral Agents for Plants.

Potato virus Y (PVY) is an important plant virus that has spread worldwide, causing significant economic losses. To search for novel structures as potent antiviral agents, a series of chiral indole derivatives containing oxazoline moieties were designed and synthesized and their anti-PVY activities were evaluated. Biological activity tests demonstrated that many chiral compounds exhibited promising anti-PVY activities and that their absolute configurations exhibited obvious distinctions in antiviral bioactivities. Notably, compound (S)-4v displayed excellent curative and protective efficacy against PVY, with EC50 values of 328.6 and 256.1 µg/mL, respectively, which were superior to those of commercial virucide ningnanmycin (NNM, 437.4 and 397.4 µg/mL, respectively). The preliminary antiviral mechanism was investigated to determine the difference in antiviral activity between the two enantiomers of 4v chiral compounds. Molecular docking indicated a stronger binding affinity between the coating proteins of PVY (PVY-CP) and (S)-4v (-6.5 kcal/mol) compared to (R)-4v (-6.2 kcal/mol). Additionally, compound (S)-4v can increase the chlorophyll content and defense-related enzyme activities more effectively than its enantiomer. Therefore, this study provides an important basis for the development of chiral indole derivatives containing oxazoline moieties as novel agricultural chemicals.

Direct Formation of Amide-Linked C-Glycosyl Amino Acids and Peptides via Photoredox/Nickel Dual Catalysis.

Glycoproteins account for numerous biological processes including those associated with diseases and infections. The advancement of glycopeptides has emerged as a promising strategy for unraveling biological pathways and discovering novel medicines. In this arena, a key challenge arises from the absence of efficient synthetic strategies to access glycopeptides and glycoproteins. Here, we present a highly concise approach to bridging saccharides with amino acids and peptides through an amide linkage. Our amide-linked C-glycosyl amino acids and peptides are synthesized through cooperative Ni-catalyzed and photoredox processes. The catalytic process generates a glycosyl radical and an amide carbonyl radical, which subsequently combine to yield the C-glycosyl products. The saccharide reaction partners encompass mono-, di-, and trisaccharides. All 20 natural amino acids, peptides, and their derivatives can efficiently undergo glycosylations with yields ranging from acceptable to high, demonstrating excellent stereoselectivities. As a substantial expansion of applications, we have shown that simple C-glycosyl amino acids can function as versatile building units for constructing C-glycopeptides with intricate spatial complexities.

N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C7-Alkylation of 4-Aminoindoles with α-Bromoenals.

The first carbene-catalyzed regio- and enantioselective indole C7-alkylation reaction between 4-aminoindoles and α-bromoenals is disclosed. The corresponding indole products could be obtained in moderate to good yields with good to excellent enantioselectivities. The evaluation of antibacterial activity against Psa revealed that nine of the C7-functionalized indoles exhibited superior inhibitory activities compared to the positive controls TC and BT. Our approach provides an efficient strategy to introduce a chiral chain into the C7 position of indole compounds, with potential applications evaluated in pesticide development.

Asymmetric Synthesis of Planar Chiral Carbonitriles and Amines via Carbene-Catalyzed Kinetic Resolution.

We have developed a catalytic method using chiral N-heterocyclic carbene (NHC) as the sole organic catalyst to synthesize planar chiral carbonitriles asymmetrically, resulting in optically pure, multifunctional compounds. The method demonstrates remarkable tolerance toward diverse substituents and substitution patterns through kinetic resolution (KR) or desymmetrization processes. The resulting optically pure planar chiral products hold significant potential for applications in asymmetric synthesis and antibacterial pesticide development.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

NHC-Catalyzed Chemo- and Enantioselective Reaction between Aldehydes and Enals for Access to Axially Chiral Arylaldehydes.

A chiral carbene-catalyzed chemo- and enantioselective reaction with racemic biaryl aldehydes and α-bromoenals is developed for access to axially chiral 2-arylbenzaldehydes through atroposelective dynamic kinetic resolution (DKR) processes. This atroposelective DKR strategy can tolerate a broad scope of substrates with diverse functionalities. The axially chiral 2-aryl benzaldehyde products generally afford moderate to good yields and enantioselectivities. The axially chiral molecules afforded from the current approach are variable through simple transformations to afford axially chiral functional molecules with excellent optical purities.

Tectorigenin Inhibits Glycolysis-induced Cell Growth and Proliferation by Modulating LncRNA CCAT2/miR-145 Pathway in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) places a heavy burden on global health. Tectorigenin (Tec) is a type of flavonoid-based compound obtained from the Chinese medical herb Leopard Lily Rhizome. It was found to exhibit remarkable anti-tumor properties in previous studies. However, the effect and molecular mechanisms of Tec in colorectal cancer have not been reported. OBJECTIVE: The objective of this study was to explore the action of Tec in proliferation and glycolysis in CRC and the potential mechanism with regard to the long non-coding RNA (lncRNA) CCAT2/micro RNA-145(miR-145) pathway in vitro and in vivo. METHODS: The anti-tumor effect of Tec in CRC was examined in cell and animal studies, applying Cell Counting Kit-8 (CCK-8) assay as well as xenograft model experiments. Assay kits were utilized to detect glucose consumption and lactate production in the supernatant of cells and animal serum. The expression of the glycolysis-related proteins was assessed by Western Blotting, and levels of lncRNA CCAT2 and miR-145 in CRC tissue specimens and cells were assessed by realtime quantitative PCR (RT-qPCR). RESULTS: Tec significantly suppressed cell glycolysis and proliferative rate in CRC cells. It could decrease lncRNA CCAT2 in CRC cells but increase the expression of miR-145. LncRNA CCAT2 overexpression or inhibition of miR-145 could abolish the inhibitive effects of Tec on the proliferation and glycolysis of CRC cells. The miR-145 mimic rescued the increased cell viability and glycolysis levels caused by lncRNA CCAT2 overexpression. Tec significantly inhibited the growth and glycolysis of CRC xenograft tumor. The expression of lncRNA CCAT2 decreased while the expression of miR-145 increased after Tec treatment in vivo. CONCLUSION: Tec can inhibit the proliferation and glycolysis of CRC cells through the lncRNA CCAT2/miR-145 axis. Altogether, the potential targets discovered in this research are of great significance for CRC treatment and new drug development.

Design, Synthesis, and Herbicidal Activity of Substituted 3-(Pyridin-2-yl)Phenylamino Derivatives.

To discover protoporphyrinogen oxidase (PPO) inhibitors with robust herbicidal activity and crop safety, three types of substituted 3-(pyridin-2-yl)phenylamino derivatives bearing amide, urea, or thiourea as side chain were designed via structure splicing strategy. Postemergence herbicidal activity assessment of 33 newly prepared compounds revealed that many of our compounds such as 6a, 7b, and 8d exhibited superior herbicidal activities against broadleaf and monocotyledon weeds to commercial acifluorfen. In particular, compound 8d exhibited excellent herbicidal activities and high crop safety at a dosage range of 37.5-150 g ai/ha. PPO inhibitory studies supported our compounds as typical PPO inhibitors. Molecular docking studies revealed that compound 8d provided effective interactions with Nicotiana tabacum PPO (NtPPO) via diverse interaction models, such as π-π stacking and hydrogen bonds. Molecular dynamics (MD) simulation studies and degradation studies were also conducted to gain insight into the inhibitory mechanism. Our study indicates that compound 8d may be a candidate molecule for the development of novel herbicides.

Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

Jianpi Huayu Decoction suppresses cellular senescence in colorectal cancer via p53-p21-Rb pathway: Network pharmacology and in vivo validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Huayu Decoction (JHD) is an herbal prescription in traditional Chinese medicine based on Sijunzi Decoction to treat patients with colorectal cancer (CRC). Its effects on the inhibition of CRC cell proliferation and tumor growth are promising; however, its multicomponent nature makes a complete understanding of its mechanism challenging. AIM OF THE STUDY: To explore the therapeutic targets and underlying molecular pathways of JHD in CRC treatment using network pharmacology techniques and in vivo validation. MATERIALS AND METHODS: The active ingredients and targets of JHD were identified, compound-target interactions were mapped, and enrichment analyses were conducted. We identified the hub targets of JHD-induced cellular senescence in CRC. The binding affinities between compounds and targets were evaluated through molecular docking. Subsequently, we conducted bioinformatic analyses to compare the expression of hub targets between colorectal tissue and normal tissue. Finally, in vivo experiments were carried out utilizing a xenograft model to assess the effects of JHD on cellular senescence biomarkers. RESULTS: Network pharmacology revealed 129 active ingredients in JHD that were associated with 678 targets, leading to the construction of compound-target and target-pathway networks. Enrichment analyses highlighted key pathways including cellular senescence. Based on this, hub targets associated with cellular senescence were determined and validated. Molecular docking indicated favorable interactions between the active components and hub targets. Gene expression and survival analysis in CRC tissue were consistent with the potential roles of hub genes. Animal experiments showed that JHD triggered cellular senescence and suppressed the growth of CRC by regulating the p53-p21-Rb signaling pathway. CONCLUSIONS: This research adopted network pharmacology, bioinformatics, and animal experiments to unveil that JHD induces cellular senescence in CRC by influencing the p53-p21-Rb pathway and senescence-associated secretory phenotypes, highlighting its potential as a CRC treatment.

Natural hair color and skin cancers: A two-sample Mendelian randomization study.

Previous observational studies have indicated an association between hair color and the risk of melanoma and keratinocyte skin cancer (KSC); however, different hair colors show inconsistent effects on skin cancers. Here, we conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between natural hair color and skin cancers by using 211 single nucleotide polymorphisms as genetic instruments from a genome-wide meta-analysis of 360,270 individuals of European ancestry. Light hair colors (red, blonde, and light brown) were associated with high levels of cutaneous melanoma (CM) and KSC (CM-inverse variance weighted [IVW] odds ratio [OR]-red: 1.034, 95% confidence interval [CI]: 1.025-1.044, P < 0.001; OR-blonde: 1.008, 95% CI: 1.003-1.014, P = 0.003; OR-light brown: 1.006, 95% CI: 1.002-1.011, P = 0.009; KSC-IVW OR-red: 1.078, 95% CI: 1.053-1.103, P < 0.001; OR-blonde: 1.024, 95% CI: 1.009-1.040, P = 0.002; OR-light brown: 1.018, 95% CI: 1.004-1.033, P = 0.01). However, dark brown hair showed an inverse causal relationship with skin cancers (CM IVW OR: 0.987, 95% CI: 0.984-0.990, P < 0.001; KSC IVW OR: 0.979, 95% CI: 0.970-0.988, P < 0.001). Black hair was associated with a decreased risk of KSC (IVW OR: 0.954, 95% CI: 0.913-0.997, P = 0.036) but showed no causal relationship with CM. The present study provides strong MR evidence of a causal association between hair color and skin cancer. Secondary MR analyses enhances result robustness by replicating findings, exploring gender-specific effects, and providing a more comprehensive understanding of the complex relationship between hair color and skin cancers. More large-scale MR studies or randomized controlled trials are required to further investigate the mechanisms of the association between hair color and skin cancers.