Search Results (84)

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases and frequently associated with poor outcomes due to resistance to conventional therapies. The epidermal growth factor (EGF)–epidermal growth factor receptor (EGFR) axis plays a central role in NSCLC progression by activating downstream phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, thereby promoting survival and proliferation. Natural compounds have emerged as promising modulators of these pathways, and oxyresveratrol (OXY), a hydroxylated analog of resveratrol, has been reported to possess antioxidant and anticancer properties, though its mechanistic role in NSCLC remains unclear. In this study, we investigated the effects of OXY in EGF-stimulated A549 and H1299 cells. OXY significantly reduced metabolic activity and decreased cell number in a dose-dependent manner and increased the proportion of apoptotic cells. Mechanistically, OXY selectively attenuated EGF-induced AKT phosphorylation while largely sparing extracellular signal–regulated kinase 1/2 (ERK1/2) activation and did not measurably alter EGFR phosphorylation or receptor trafficking dynamics. These findings indicate that OXY exposure is associated with AKT-selective signaling suppression and reduced cellular fitness in NSCLC cells, without evidence of direct EGFR inhibition. Further genetic rescue and pathway-epistasis studies are required to establish causal dependency on AKT signaling and to support in vivo validation. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. Natural compounds, especially curcumin and its derivatives, have gained increasing attention as potential anticancer agents due to their ability to target multiple molecular pathways involved in tumor progression. This review critically evaluates the current preclinical and translational evidence supporting curcumin and its derivatives as monotherapeutic agents in HNC, with particular emphasis on oral cancer. We integrate the available evidence to assess the biological rationale, therapeutic potential, and current limitations of curcumin-based approaches. The molecular mechanisms underlying their antitumor activity are discussed, including modulation of EGFR/ERK and PI3K/Akt signaling pathways, inhibition of NF-κB and STAT3 activation, induction of apoptosis, regulation of oxidative stress, and suppression of epithelial–mesenchymal transition and tumor invasiveness. In addition, we address the impact of curcumin on the tumor microenvironment and its role in overcoming intrinsic cellular resistance mechanisms. The review also highlights advances in drug delivery strategies, such as nanoformulations, that are designed to improve curcumin’s bioavailability and therapeutic efficacy. By critically integrating current evidence, this review highlights both the promise and the challenges associated with curcumin-based monotherapy in HNC, emphasizing the need for more robust and clinically relevant studies to support future translation. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

Periplaneta americana extract can promote wound healing and may play an important role in skin wound healing. In this study, we identified a peptide (DL-13) from Periplaneta americana L. and explored its role and mechanisms in skin wound healing. In vitro, the effects of DL-13 on proliferation, migration, and related gene/protein expression in HaCaT keratinocytes were assessed via qRT-PCR and Western blot. In vivo, rat wound healing assays confirmed its efficacy. Results showed DL-13 accelerated rat wound healing. In in vitro studies, DL-13 activated EGFR and its downstream PI3K/AKT/mTOR, ERK/MAPK, and JAK2/STAT3 pathways, upregulated EMT-related proteins (N-cadherin, MMP-2, p-FAK, β-catenin), partially regulated macrophage cytokine secretion, and promoted HaCaT proliferation/migration, thereby facilitating re-epithelialization at skin injury sites. Overall, DL-13 may enhance the function of HaCaT cells by activating the EGFR signaling pathway and regulate inflammatory factors in macrophages, thereby promoting the healing of skin wounds in rats. The results of this study will lay an experimental and scientific foundation for the discovery of new compounds for wound healing and their application. Full article

Background: Patients with type 2 diabetes mellitus (T2DM) undergoing cardiac surgery represent a high-risk population characterized by substantial cardiometabolic stress and increased susceptibility to postoperative heart failure, renal dysfunction, and unplanned rehospitalization. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors provide established cardiorenal protection in ambulatory populations, their perioperative impact in cardiac surgery cohorts remains insufficiently defined. Methods: In a single-center retrospective cohort of 620 T2DM patients, inverse probability of treatment weighting and time-dependent Cox regression were applied to account for perioperative treatment interruption and delayed postoperative reinitiation when evaluating the association between chronic SGLT2 inhibitor therapy and 12-month rehospitalization risk. To provide biological context for the observed clinical associations, target-driven systems pharmacology, molecular docking against SGLT2, NHE1, AMPK, and NLRP3, and protein–protein interaction (PPI) network analysis were performed. Hub proteins were identified using Maximal Clique Centrality, followed by functional enrichment (GO/KEGG) analysis. Results: Chronic SGLT2 inhibitor therapy was associated with reduced first rehospitalization (HR 0.64; 95% CI 0.48–0.85; p = 0.002) and a lower cumulative rehospitalization burden (IRR 0.61; 95% CI 0.46–0.82; p = 0.001), primarily driven by heart failure-related and metabolic phenotypes. Molecular docking analyses identified favorable binding with SGLT2 and additional cardiometabolic and inflammatory targets, including NHE1, AMPK, NLRP3, IKKβ, IL-6Rα, and PPAR isoforms, suggesting modulation of myocardial ion homeostasis, metabolic resilience, and inflammatory signaling. PPI analysis identified eight hub proteins (AKT1, MTOR, STAT3, EGFR, PIK3CA, SRC, MAPK1, and MAPK3) significantly enriched in PI3K/AKT, MAPK/ERK, and ErbB signaling pathways. Conclusions: Chronic SGLT2 inhibitor therapy was independently associated with reduced postoperative rehospitalization and cumulative event burden in T2DM patients undergoing cardiac surgery. Integrated in silico analyses offer mechanistic hypotheses consistent with the observed clinical associations. These findings suggest that structured perioperative SGLT2 inhibitor management may contribute to improved postoperative outcomes, while prospective validation in future studies would strengthen these findings. However, given the retrospective observational design, these findings should be interpreted as associative rather than causal. Full article

HIV latency, driven by a complex interplay of host factors, remains a key barrier to viral clearance. Current latency-reversing agents (LRAs) demonstrate limited efficacy and specificity, and none have been approved for clinical use. Although natural products have shown promise as LRAs, the therapeutic potential of fungal metabolites remains underexplored. Candida albicans, a prevalent human commensal and opportunistic pathogen, produces diverse secondary metabolites that can influence host pathways, affecting latency dynamics. This study aimed to investigate the latency-modulating potential of secondary metabolites of C. albicans using an integrative network pharmacology and computational pipeline. C. albicans secondary metabolites were retrieved from the literature, screened for drug-likeness, and mapped to human targets and biological pathways annotated in HIV latency. Key metabolites, hub genes, and pathways were systematically characterized through network and computational analyses. Six drug-like candidates, identified from 185 absorption, distribution, metabolism, excretion, and toxicity (ADMET)-screened metabolites, collectively mapped to 369 human genes with a 6.5% overlap in HIV latency (176 shared and 20 hub genes). These overlapping genes were significantly enriched for signal transduction, membrane localization, and adaptive responses to chemical stimuli. Kyoto encyclopedia of genes and genomes (KEGG) enrichment revealed oncogenic diseases (non-small cell lung, pancreatic, and prostate cancers) and latency-associated cascades, including PD-L1/PD-1, HIF-1, Ras, PI3K-Akt, calcium, and cAMP signaling. Six hub targets (MAPK1, PIK3CA, MAPK3, EGFR, MTOR, and AKT1) were consistently annotated within the top 30 KEGG pathways and displayed strong binding affinities for MET 15 and MET 119. Molecular dynamics (MD) simulations confirmed favorable binding free energies (BFEs) and stable conformational dynamics for the top-ranked metabolite MET 15. C. albicans secondary metabolites preferentially target oncogenic signaling networks central to HIV latency maintenance, notably PI3K/AKT/MTOR and MAPK/ERK, which regulate cell survival, metabolic homeostasis, and viral transcriptional repression. MET 15 is a top-ranked candidate metabolite for HIV latency-reversing therapeutics and warrants experimental validation in established latency models. Full article

Human papillomavirus type 16 (HPV16) persistence relies on early viral mechanisms that synchronize oncogenic signaling with immune evasion, with the E5 oncoprotein serving as a central regulator of the viral cycle and the initiation of cell transformation. This review integrates current evidence on how E5 reconfigures host cell dynamics: first, by hijacking signaling pathways such as EGFR, MAPK/ERK, and PI3K/AKT to drive keratinocyte proliferation and survival; and second, by organizing a multi-step immune evasion strategy. We detail how E5 suppresses innate antiviral responses, specifically by repressing IFN-κ and IFN-β via interference with IRF1, TGF-β/SMAD, STING, and MAVS signaling. Simultaneously, E5 interferes with the adaptive immunity by disrupting MHC-I trafficking and impairing MHC-II maturation. Furthermore, preclinical studies utilizing various vaccine platforms targeting HPV16 E5 have demonstrated the capacity to reduce tumor burden and significantly increase survival rates. By integrating these molecular and immunological checkpoints, we highlight the role of E5 in sustaining viral persistence and underscore its potential as a high-value target for next-generation immunotherapeutic and vaccine-based strategies. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related deaths in advanced disease, and activating KRAS/NRAS mutations limit the use of anti-EGFR antibodies to RAS–wild-type tumors. The cellular prion protein (PrP^C) has been linked to aggressive and chemoresistant CRC, but its extracellular partners and functional relevance in KRAS-mutant disease are not fully defined. Here, we examined extracellular PrP^C complexes and PrP^C-associated signaling in CRC cell lines and xenografts using a neutralizing PrP^C monoclonal antibody. Across a CRC panel that included SNU-C5/WT and its 5-fluorouracil- and oxaliplatin-resistant derivatives, HT-29 (KRAS–wild-type), and HCT-8 and LoVo (KRAS-mutant), co-immunoprecipitation showed that PrP^C forms complexes with the 37/67 kDa laminin receptor (RPSA), with PrP^C–RPSA association particularly increased in KRAS-mutant HCT-8 and LoVo cells. PrP^C protein levels were higher in KRAS-mutant HCT-8, SW620, and SNU-407 cells than in HT-29, and PrP^C neutralization reduced viability in all four lines. Accordingly, we assessed upstream RAS activity and found that active RAS (RAS-GTP) was higher in KRAS-mutant cells than in HT-29, and PrP^C treatment was associated with reduced RAS-GTP levels. In the same KRAS-mutant setting, basal AKT phosphorylation exceeded that in HT-29, and PrP^C treatment lowered AKT phosphorylation without changing total AKT. Moreover, PrP^C treatment was associated with reduced ERK1/2 phosphorylation in KRAS-mutant cells, suggesting attenuation of downstream RAS pathway output. These signaling changes coincided with a decrease in the S-phase fraction and an increase in G1. In an HCT-8 (KRAS G13D) xenograft model, PrP^C monotherapy inhibited tumor growth in a dose-dependent manner, and 5-fluorouracil (5-FU) monotherapy produced an intermediate effect. The combination of PrP^C (10 mg/kg) and 5-FU (20 mg/kg) yielded the greatest tumor growth inhibition among the tested regimens. Consistent with this enhanced tumor control, immunofluorescence of xenograft tissues showed that PrP^C, particularly with 5-FU, reduced intratumoral PrP^C and PCNA and decreased CD31-positive microvessels and α-SMA–positive vessel structures. Taken together, these findings suggest that extracellular PrP^C supports RAS–AKT signaling, proliferation, and tumor-associated angiogenesis in KRAS-mutant colorectal cancer, and that PrP^C neutralization additively enhances 5-fluorouracil activity in KRAS-mutant models. The data provide a preclinical basis for evaluating PrP^C antibodies in combination with fluoropyrimidine-based regimens in patients with KRAS-mutant CRC. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

Lung cancer is a leading cause of cancer mortality worldwide. Targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a significant advance in the management of lung cancer. However, their long-term efficacy is often limited by acquired resistance, particularly due to the T790M mutation, highlighting the need for novel EGFR-TKIs. Although compounds derived from Centella asiatica have demonstrated anticancer potential, their role in EGFR inhibition has not yet been reported. In this study, we investigated the inhibitory activity of two primary constituents, asiaticoside and asiatic acid, against wild-type and double-mutant (L858R/T790M) EGFR, as well as the anticancer effects of the more potent compound in lung cancer cells. A kinase activity assay revealed that asiatic acid potently inhibited both wild-type and double-mutant EGFR, whereas asiaticoside showed minimal inhibitory activity. Molecular docking demonstrated that asiatic acid bound to the ATP-binding pocket of both EGFR forms with binding energies superior to those of erlotinib and osimertinib. Treatment with asiatic acid significantly (i) reduced viability of A549 and H1975 cells while remaining non-toxic to BEAS-2B normal lung cells, (ii) enhanced cancer cell apoptosis, (iii) suppressed extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) signaling pathways, and (iv) inhibited EGFR activation in A549 and H1975 cells. These results suggest that asiatic acid is a promising lead compound for anticancer drug development. Full article