Abstract Background India has made substantial progress in reducing Plasmodium falciparum malaria cases and has set a target to eliminate malaria by 2030. Although ACT treatment remains effective, tracking regional differences in genetic variants associated with antimalarial resistance is required for effective drug policy implementation. Methods We analysed 238 P. falciparum clinical samples from six Indian states by sequencing 15 parasite genes associated with reduced drug effectiveness. The method involved nanopore sequencing of target gene amplicons derived from dried blood spots using a highly sensitive PfMDR15 surveillance panel. Results India’s historical policy of artesunate-sulfadoxine-pyrimethamine in central India and artemether-lumefantrine in the Northeast has shaped contrasting resistance profiles. In the Northeast, chloroquine resistance persisted at high frequency (Pfcrt K76T and CVIET haplotype; Pfaat1 S258L), alongside quintuple and sextuple Pfdhfr–Pfdhps haplotypes conferring complete sulfadoxine-pyrimethamine resistance. Central India showed variable chloroquine resistance (parasites largely retained wild-type Pfcrt) and emerging lumefantrine tolerance (Pfmdr1 Y184F, Pfaat1 S258L). Interestingly, Delhi (Central India) parasites resembled profiles from the distant Northeast, which borders South East Asia. The detection of Pfaat1 S258L, previously reported only from Africa and associated with reduced lumefantrine susceptibility, suggests convergent evolution under ACT partner-drug pressure. No WHO-validated Pfk13 artemisinin resistance mutations were detected, supporting continued efficacy of artemisinin-based combination therapy (ACT). Conclusion India’s resistance landscape is fragmented, with signals of expanding lumefantrine tolerance and importation or evolution of globally relevant mutations. These findings highlight the importance of integrating molecular genomic surveillance into malaria control policy to monitor and protect ACT effectiveness and advance malaria elimination.

Plasmodium falciparum and P. vivax are parasites responsible for most malaria cases globally. In areas where these species co-exist, individuals gain protection from P. vivax more rapidly, and important biological differences between species may impact the immune response. CD4 T cells are key drivers of immunity to malaria, both as effector and helper cells, with T-follicular helper (Tfh) cells having key roles in antibody development. Comparative studies on CD4 T cell responses between these species are limited. We assessed CD4 T cells in adults with either P. falciparum or P. vivax malaria. Activation and proliferation of CD4 T cells were measured ex vivo, and functional capacity was determined by intracellular cytokine staining using flow cytometry. The phenotype, activation and proliferation of CD4 T cells and effector CD4 T cell subsets were comparable between species. However, within the peripheral (p)Tfh cell compartment, there was some evidence for species-dependent activation with relative increased pTfh1 cells in P. falciparum infection. Additionally, in P. falciparum, increased IL-10 production was detected, including within IL-21 producing CD4 T cells. While activation and function of CD4 T cells in malaria are largely comparable, some species-dependent responses are detected within the pTfh cell compartment that may impact antibody development.

α-thalassemia, a hereditary disorder, common in malaria-endemic regions, provides selective advantage by conferring partial protection against severe Plasmodium falciparum malaria. This study investigated the distribution of α-thalassemia genotypes and Plasmodium falciparum carriage among 1401 asymptomatic individuals aged 1-60years, across Ghana's coastal, forest, and Sahel savanna ecological zones. DNA was extracted from archived dried blood spots and genotyped for α-thalassemia using multiplex PCR, while malaria was detected through RDT, microscopy, and PCR. Participants from the forest zone had the highest malaria prevalence by PCR (36.5%) compared to those in the Sahel savannah zone (27.6%), and coastal zone (23.5%), p < 0.0001. In the coastal zone, 54.3% (482/887) of participants had the wild type genotype (αα/αα), 41.8% (371/887) were heterozygous carriers (-α/αα), and 3.8% (34/887) were homozygous recessive for α-thalassemia (-α/-α). In the forest zone participants had 66.0% (134/203) wild type, 30.5% (62/203) heterozygous, and 3.5% (7/203) homozygous individuals, while participants in Sahel savannah recorded 62.7% (195/311) wild type, 31.5% (98/311) heterozygous, and 5.8% (18/311) homozygous recessive genotypes. There were higher odds of having asexual parasites (Odds Ratio = 1.23) and an increased odds (Odds Ratio = 1.46) of gametocyte carriage in the homozygous recessive group compared to the wild type, p = 0.447 but there were no statistically significant association observed between α-thalassemia genotype and the presence of asexual P. falciparum stages.

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum malaria that causes coma and frequently death in patients. In malaria-endemic settings, a large percentage of the population presents with incidental P. falciparum malaria parasitemia. In the absence of specific biomarkers for CM, when these individuals suffer from bacterial or viral infections causing coma, they are frequently misdiagnosed with CM. We have tested the specificity for CM of two candidate biomarkers for severe malaria, Angiopoietin-like 4 and Inhibin-βE, which are secreted by endothelial cells in response to P. falciparum infected erythrocytes. The levels of these biomarkers were determined retrospectively in the plasma of a cohort of 379 Kenyan children including cases of severe malaria caused by CM, respiratory distress or severe anemia, as well as cases of non-traumatic coma of unknown cause. Angiopoietin-like 4 and Inhibin-βE showed high specificity for severe malaria, including CM (AUC 0.82), respiratory distress (AUC 0.86) and severe anemia (AUC 0.85), when compared to acute non-traumatic coma of non-malarial etiology. Specificity was further increased when the biomarkers were used in combination with platelet levels (AUC 0.96). Angiopoietin-like 4 and Inhibin-βE are also predictors of death by CM (AUC 0.85). Angiopoietin-like 4 and Inhibin-βE could be developed as a diagnostic tool for the differentiation of comatose patients with CM from other causes of coma.

Malaria remains a global health concern, with Africa bearing the highest global burden of malaria, as Plasmodium falciparum malaria remains the leading cause of malaria-related mortality on the continent. The transmission dynamics of malaria are shaped by a combination of factors, including climate conditions, economic constraints, geographic variability, human activities, and security instability. Owing to repeated infections and widespread implementation of early interventions, there has been a notable rise in cases of clinically atypical malaria and asymptomatic Plasmodium carriers, which increases the risk of misdiagnosis and underdiagnosis. Despite these challenges, African nations have made substantial progress in malaria control and elimination. Key advancements include, increased distribution of insecticide-treated nets use, increased indoor residual spraying, widespread rapid diagnostic tests, intermittent preventive treatment in vulnerable populations, deployment of artemisinin-based combination therapies (ACTs), and of late, the deployment of malaria vaccines to children under 5years. Between 2000 and 2022, the WHO African Region reported a 40% reduction in malaria incidence and a 60% decline in mortality. Nonetheless, the continent faces emerging threats that could hinder further progress. These include persistent poverty, the effects of climate change, inadequate healthcare infrastructure and coverage, increased outdoor transmission linked to changing mosquito behavior, the appearance of new vector species, and rising resistance to both antimalarial drugs and insecticides. To address these challenges, a multi-faceted strategy is essential. This includes cross-border prevention and control efforts, expansion of seasonal malaria chemoprevention programmes, identification of molecular markers of resistance, development of novel antimalarial agents, and scaled-up implementation of vaccines such as RTS,S/AS01 and R21/Matrix-M. Implementation of approaches employed by countries such as China in malaria elimination and strengthening global-Africa cooperation in the fight against malaria could further accelerate progress. This review aims to provide a comprehensive overview of global malaria with a focus on Africa and global efforts toward the continent's malaria elimination goals.

Amodiaquine-artesunate is one of the recommended options by the Angolan National Malaria Control Program for the treatment of uncomplicated malaria and for malaria seasonal chemoprevention. CYP2C8 is a critical enzyme in the metabolism of amodiaquine. The CYP2C8 gene harbors alleles coding for less active enzymes that have been linked to amodiaquine-associated adverse events. In this work, we analyzed the prevalences of the CYP2C8 main alleles in a sample of the Angolan population. We found an expected robust frequency of a very-low-activity allele, CYP2C8*2 (18.2%) but also the unusual presence of alleles CYP2C8*3 (1%) and CYP2C8*4 (0.5%). Together, these alleles were seen in a non-negligible group of Plasmodium falciparum malaria patients and children under amodiaquine-based therapies and prophylactic strategies.

The efficacy of artesunate + amodiaquine (ASAQ) and artemether + lumefantrine (AL) for treating malaria was investigated in Madagascar in 2020. A randomized parallel-group study was conducted at four health centers (Antsenavolo, Vohitromby, and Matanga in the southeastern region and Ankazomborona in the northwestern region). The therapeutic efficacy and safety of ASAQ and AL were assessed using the WHO protocol, with a 28-day follow-up period. Children aged 6 months to 14 years with uncomplicated Plasmodium falciparum (P. falciparum) malaria were randomly assigned to receive either ASAQ or AL. Genotyping assays for the pfK13 gene were conducted on P. falciparum isolates obtained from dry blood samples collected on Day 0. Of 765 enrolled patients, 709 (92.7%) reached the study endpoint. Among the per-protocol population, crude adequate clinical and parasitological response (ACPR) rates were 99%, 99%, 100%, and 100% for Antsenavolo, Vohitromby, Matanga, and Ankazomborona, respectively, in the ASAQ group and 98%, 91%, 90%, and 100% for the same locations, respectively, in the AL group. Polymerase chain reaction-corrected ACPR rates were 100% for the ASAQ group at all study sites, whereas for the AL group, they were 98.8% in Antsenavolo, 97.6% in Vohitromby, 100% in Matanga, and 100% in Ankazomborona. Day 3 slide positivity rates were 0%, 1%, 1%, and 0% for Antsenavolo, Vohitromby, Matanga, and Ankazomborona, respectively. During follow-up, mild and moderate adverse events, including gastrointestinal issues (abdominal pain and vomiting) and headache, were reported in 10.2% (72/709) of patients. Of 727 samples successfully analyzed for pfK13, no mutation associated with artemisinin resistance was observed. The study results reveal that ASAQ and AL remain safe and efficacious for treating uncomplicated P. falciparum malaria in Madagascar.

pLDH to identify severity in imported malaria: Implementing smartphone video analysis for rapid clinical decision-making.

Residual antimalarial drug concentrations before treatment in malaria patients in Asia and Africa: A systematic review and meta-analysis depicting its implication for drug pressure.

Data on long-term sequelae after severe imported Plasmodium falciparum malaria in adults are scarce in non-endemic settings. We aimed to quantify early and medium term renal and neurological outcomes and identify prognostic factors. Therapeutic strategies have evolved with widespread intravenous artesunate, yet survivorship data remain limited. We performed a retrospective study of cases of severe malaria at the University Hospital of Marseille (France) between January 2018 and December 2024. This study is a single-centre retrospective cohort with prospective follow-up using standardised questionnaires. Adults meeting the criteria for severe falciparum malaria were included. The primary endpoint was a composite of renal impairment and/or neurological sequelae assessed at day 28 (D28) and at remote post-discharge follow-up. Patient-reported outcomes were collected at one year. Associations with baseline features were tested using the Fisher's exact and Wilcoxon-Mann-Whitney tests. Among 474 malaria cases, 66 (13.9%) were severe; of these, 57 met inclusion criteria. Fifty-seven of them were included. All received intravenous artesunate with oral step-down; 35% required ICU care. At D28, 6/41 patients (14.6%) had sequelae (four renal, one neurological, one both). Sequelae at D28 were associated with neurological failure (66.7% vs. 14.3%; p = 0.015), severe metabolic acidosis (50.0% vs. 2.9%; p = 0.007) and renal impairment at admission (83.3% vs. 2.9%; p < 0.001). At remote follow-up, 6/33 patients (18.2%) had sequelae (two renal, three neurological, one both), associated with older age (61.0 ± 5.3 vs. 39.8 ± 15.8 years; p = 0.008), D3 blood smear positivity (66.7% vs. 11.5%; p = 0.012), neurological failure (66.7% vs. 18.5%; p = 0.034) and renal impairment (50.0% vs. 7.4%; p = 0.031). No deaths or relapses occurred. At one year, patient-reported outcomes (n = 14) showed persistent symptoms in 8/14, chiefly fatigue and cognitive complaints. In a high-resource, non-endemic setting, renal and neurological sequelae after severe imported malaria are frequent at D28 and persist in nearly one-fifth of cases during post-discharge follow-up. Neurological failure, metabolic acidosis, renal impairment at presentation, older age and D3 blood smear positivity identify patients at risk and support risk-stratified post-discharge follow-up.

The growing number of international travelers aged ≥60 years reflects global demographic changes and improved life expectancy. However, this group faces specific health risks due to age-related physiological changes and comorbidities, which may influence the presentation and management of travel-related illnesses. This study aimed to describe the epidemiological and clinical characteristics of imported diseases among older travelers compared with younger adults in Spain. A retrospective observational study was conducted using data from the Spanish National Network (+Redivi). We analyzed records of travelers who sought medical care after returning to Spain between January 2011 and December 2023 in six different centres. Demographic data, travel history, and final diagnoses were compared between individuals aged ≥60 years and those <60 years. Descriptive and inferential statistics were performed using R software (v4.2.2). Among 29,573 total tourist travellers , 1,230 (4.2%) involved individuals aged ≥60 years. In the traveler subgroup, 546 older and 7,704 younger adults were compared. Older travelers more often undertook very short (<15 days, 46.3%) or prolonged (>360 days, 11.4%) trips and sought pre-travel advice less frequently (36.1%, p<0.001). Sub-Saharan Africa and South America were the main regions of infection acquisition. Gastrointestinal disorders were the leading cause of consultation in all groups, but older adults more frequently presented with skin (22.2%) and respiratory (3.8%) symptoms. The most frequent diagnoses in the older cohort included Plasmodium falciparum malaria (4.8%), strongyloidiasis (3.3%), and chikungunya (3.5%). Older travelers represent a distinct and growing population within travel medicine, characterized by specific patterns of exposure and infection. These findings highlight the need for tailored pre-travel counseling and preventive strategies that consider comorbidities, vaccine limitations, and extended travel durations to reduce morbidity in this vulnerable group.

Malaria remains a major cause of morbidity and mortality in sub-Saharan Africa. Severe Plasmodium falciparum malaria is primarily driven by parasite sequestration in deep vascular tissues. Standard diagnostic tools, such as peripheral parasitaemia determination, do not always reflect the total parasite burden. Plasma Plasmodium falciparum Histidine-Rich Protein 2 (PfHRP2) level has emerged as a potential biomarker for estimating total parasite biomass, which may better reflect disease severity than peripheral parasitaemia. However, it is still unclear how PfHRP2-estimated parasite biomass varies across different clinical malaria syndromes, how well it predicts severity compared to circulating parasitaemia, and how prior antimalarial treatment influences these measures. Addressing these gaps is critical to improving severity assessment and guiding timely interventions. Data from 118 children diagnosed with cerebral malaria (CM, n = 58), severe malaria anaemia (SMA, n = 28), or uncomplicated malaria (UM, n = 32) were collected in five referral hospitals in Accra from 2012 to 2016. Total parasite burden (PTot) was estimated using PfHRP2-based biomass measurement while the circulating parasite burden (PCir) was determined from peripheral parasite density. The sequestered parasite burden (PSeq), which represent the difference between PTot and PCir, was also evaluated. Additionally, the impact of prior antimalarial treatment on parasite burden was assessed. PTot and PSeq were consistently higher than PCir in severe malaria syndromes. In UM, PTot and PCir were similar, while the median PCir was lower in CM than in UM, suggesting greater sequestration in severe disease. After regaining consciousness, CM patients exhibited decreased PTot and PSeq values compared to their values at initial clinical evaluation. Higher PSeq estimates were associated with coma. Prior antimalarial treatment also reduced PCir but did not significantly change PTot. PfHRP2-derived total parasite biomass demonstrated a stronger association with severe malaria syndromes than peripheral parasitaemia. Accounting for prior antimalarial treatment is essential, as it may lower circulating parasite counts without affecting total biomass. Incorporating total parasite biomass assessments into clinical evaluation could enhance disease severity classification and inform timely interventions in endemic regions.

Two licensed vaccines block Plasmodium falciparum malaria sporozoites through anticircumsporozoite protein antibodies. In animal models, intradermal (ID) sporozoites are more readily blocked than intravenous sporozoites. We hypothesized that this complicates human studies, where infectious mosquito bites deliver a mixture of ID and venous sporozoites. Here, to test whether vaccine efficacy varies by route of inoculation, we undertook a phase 2b open, randomized controlled trial, recruiting healthy volunteers in Kenya for randomization to the circumsporozoite protein-based R21/Matrix-M vaccine (n = 38), thrombospondin-related adhesive protein fused to a multi-epitope string (ME-TRAP)-based vaccines (n = 24) or to control (n = 18). We enrolled 37 of these volunteers to controlled human malaria infection (CHMI) using ID or direct venous injection (DVI) of sporozoites, with PCR monitoring of parasitemia. Systemic and local postvaccination adverse events and systemic CHMI-related events were detected in 4.8%, 12.9% and 72.9% of volunteers, respectively, most commonly fever, headache and fatigue. No serious or severe adverse events were seen. Seven of 8 (88%) control volunteers and 11 of 12 (92%) ME-TRAP vaccinated volunteers, but none of the 12 R21 vaccinated volunteers receiving ID challenge met the prespecified treatment criteria for the primary endpoint. However, five of five R21 vaccinated volunteers receiving DVI sporozoites met the primary endpoint (P < 0.0005 by log rank across all groups). Secondary efficacy outcomes were similar; that is, R21 vaccinated volunteers receiving ID challenge did not meet any secondary endpoints, whereas volunteers for other groups met secondary endpoints between days 7 and 21 (P < 0.0005, P = 0.0001, P = 0.0007 and P < 0.0005 by log rank for time to parasitemia >20, >500, >1,000 and >10,000, respectively). R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites. CHMI is used in clinical development to select efficacious vaccines and to define correlates of efficacy. Correlates of efficacy for antibodies to sporozoites should also be assessed by separate DVI and ID challenges. The study was registered with ClinicalTrials.gov ( NCT03947190 ) and PACTR ( PACTR202108505632810 ).

Objective: Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium ( P. ) falciparum malaria. This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system (FAERS). Methods: This is a retrospective analysis on 15-year data of artemether-related adverse effects (AEs) retrieved from the FAERS. AEs were classified according to System Organ Class (SOC) and Preferred Terms (PT). Signal detection was performed using Reporting Odds Ratios (ROR), Proportional Reporting Ratios (PRR), and Empirical Bayes Geometric Mean (EBGM). Stratified analyses examined the impact of demographic factors such as sex, age, and time-to-onset. Temporal patterns and associated risk factors were also investigated. Results: Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs, exhibiting significantly elevated RORs (males: ROR 381.36, 95% CI 247.06-588.60; females: ROR 455.11, 95% CI 286.43-723.12). Sex-specific differences were evident, with females showing a higher incidence of reproductive-related AEs, including spontaneous abortion and premature labour. Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration, indicating a rapid onset. The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders. Conclusions: Artemether is associated with a notable frequency of early-onset AEs, particularly hematological and hepatobiliary disorders. The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches. Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.

Malaria epidemiology, clinical characteristics, and concurrent infections in Delhi, India: A hospital-based study.

Diversifying antimalarial treatment for uncomplicated Plasmodium falciparum malaria in Uganda.

&amp;lt;i&amp;gt;Background: &amp;lt;/i&amp;gt;Malaria remains a significant global health challenge, particularly in children in endemic regions. This study aimed to examine the prevalence, risk factors, and predictive indicators of hypoglycemia in children with uncomplicated Plasmodium falciparum malaria.&amp;lt;i&amp;gt; Methods: &amp;lt;/i&amp;gt;A cross-sectional study was conducted at the Urban Community Health Center of Anonkoua-Kouté in Abidjan, Ivory Coast. Thirty-eight Black African children aged 3-14 years with uncomplicated P. falciparum malaria were included. Parasitemia, leukocyte count, blood hemoglobin concentration, and glycemia were also evaluated. The Spearman coefficient was used to analyze non-parametric distributions. A receiver operating characteristic (ROC) curve was used to determine the parasitemia threshold for optimal prediction of hypoglycemia risk. &amp;lt;i&amp;gt;Results: &amp;lt;/i&amp;gt;The prevalence of hypoglycemia was 34.2%, with a mean blood glucose level of 4.17 mmol/l. An inverse correlation was observed between glycemia and parasitemia. ROC curve analysis demonstrated an optimal hypoglycemic risk with a sensitivity of 85% and specificity of 68% for a parasitemia threshold of 3,725/µL. No statistically significant associations were identified between glycemia and leukocyte count, hemoglobin level, or patient age. &amp;lt;i&amp;gt;Conclusion: &amp;lt;/i&amp;gt;This study revealed a high prevalence of hypoglycemia in children with uncomplicated malaria, which was associated with elevated parasitemia levels. The importance of this factor in clinical settings arises from its potential impact on patient management and development of treatment strategies. The identified parasitemia threshold may serve as a critical indicator for evaluating treatment efficacy and assessing potential complications of malaria. Further research is warranted to validate these findings in larger multisite studies and to explore additional confounding factors.

Eukaryotic cytochrome (cyt) c is a highly conserved mitochondrial protein central to cellular respiration, featuring a covalently attached hexacoordinate heme whose redox potential is tuned by axial His/Met ligands and surrounding residues to support electron transport chain (ETC) function. We have identified an unrecognized lineage of eukaryotic cyt c homologs in Apicomplexa, a phylum of intracellular pathogens that includes Plasmodium falciparum malaria parasites. P. falciparum cyt c-2 (Pfcyt c-2) exemplifies this divergent lineage and has an unusual pentacoordinate heme despite conservation of His/Met ligands. We determined that Pfcyt c-2 has a redox potential of −278 mV that is over 500 mV lower than canonical cyt c homologs (+250 mV) and contradicts a conserved ETC role. This anomalous redox potential is lower than any natural monoheme c-type cyt. Nevertheless, Pfcyt c-2 displays canonical thermostability and low-level peroxidase activity, while showing signs of elevated structural heterogeneity. These results reveal a new clade of eukaryotic cyt c variants with divergent biochemical properties and biological roles, opening new scaffolds for mechanistic discovery and redox engineering.

BackgroundThrombocytopenia commonly accompanies Plasmodium falciparum (P. falciparum) malaria, yet the role of impaired megakaryopoiesis and platelet production remains unclear. This study examined how P. falciparum–infected red blood cells (pRBCs) and their extracellular vesicles (EVs) modulate megakaryocytic differentiation and platelet-like particle (PLP) formation.MethodsMEG-01 cell line, a human megakaryoblastic leukaemia model, was differentiated with phorbol 12-myristate 13-acetate (PMA) in the presence or absence of fetal bovine serum (FBS) and co-cultured with pRBCs, normal RBCs (nRBCs), or their EVs (nRBC-EVs/pRBC-EVs). Changes in cell phenotype, adhesion, and gene expression were analyzed by flow cytometry, confocal microscopy, and qPCR. PLP functionality was assessed by clotting assays, and cytokine secretion was quantified using cytometric bead array.ResultspRBCs transiently adhered to MEG-01 cells but suppressed megakaryocytic marker expression, downregulated NOTCH3, and altered apoptosis- and stress-related genes. PLP production increased under some conditions, but clotting activity was impaired, indicating reduced functionality. In contrast, RBC-EVs, particularly pRBC-EVs, were internalized but induced minimal transcriptional or functional changes. Cytokine profiling revealed that pRBCs and their EVs selectively increased IL-8, RANTES, and MCP-1 levels.ConclusionsIntact pRBCs strongly inhibit megakaryocytic differentiation and disrupt PLP function through transcriptional dysregulation and inflammatory activation, whereas under our experimental conditions, RBC-EVs exert milder modulatory effects. These findings highlight defective platelet production as a novel mechanism contributing to malaria-associated thrombocytopenia.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12936-025-05743-6.

Plasmodium falciparum malaria is fatal if left untreated. Treatment is hampered by drug-resistant variants of the malaria parasite, highlighting the need to explore unique pathways for the development of new drugs with different mechanisms of action. Kinases in the inositol phosphate signaling pathway (IPP), and its products play many important roles in energy metabolism and signal transduction, making them attractive drug targets. In this exploratory study we investigated the potential of P. falciparum IPP as a novel and attractive pathway for antimalarial drug discovery, employing a combined in silico and molecular approach. The sequences and structures of the putative P. falciparum inositol phosphate kinases were characterized in silico. Experimental validation across laboratory strains and a clinical isolate confirmed the p.Pro375Gln substitution in IPMK1, providing the first evidence of this variant in field isolates. We provide molecular evidence of the existence of IPP genes in P. falciparum and suggest that targeting this pathway could be detrimental to the parasite. We identify P. falciparum inositol polyphosphate multikinase (IPMK) as a promising drug target due to its unique sequence and structural characteristics. These results serve as a guide for future experimental validation.