The Influence of Sexual Polymorphism on Metabolomics and Biological Activities of Pawpaw ( <i>Carica papaya</i> )

Pawpaw ( Carica papaya ) is an economically important tropical crop valued for its nutritional fruit. The leaf is eaten as salad, soup, or tea. Various parts of the pawpaw are used to treat diseases. However, no studies have examined how sexual polymorphism (male, female, and hermaphrodite) affects the plant’s metabolome and bioactivities. This study evaluated sex‐based differences in metabolomes and bioactivities of extracts from leaves and roots of male and female C. papaya . Metabolome dereplication employed ultra‐high‐performance liquid chromatography coupled with mass spectrometry (UHPLC–MS/MS) analysis and phytochemical screening. Bioactivity assessments included DPPH (antioxidant), protein denaturation (anti‐inflammatory), SYBR Green (antimalarial), and agar well diffusion (antimicrobial) assays. Phytochemical screening revealed significant sexual dimorphism. Female leaf extract (FPL) contained the highest diversity (7 classes), phenolic compounds (11.27 ± 0.04 mg/100 mg GAE), and flavonoids (19.71 ± 1.002 mg/100 mg QE). UHPLC–MS identified 11 compounds in male leaves versus 7 in the female, with sex‐specific metabolites including rutin and lutein in males and daucosterol in females. Common metabolites included isorhamnetin 3‐O‐β‐D‐glucopyranoside and dihydrocurcumin. Male leaf and root extracts showed superior antimalarial activity (IC 50 = 20.00 ± 1.417 μg/mL) and anti‐inflammatory activity (IC 50 = 187 μg/mL), respectively. FPL demonstrated the highest antioxidant activity (IC 50 = 13.85 ± 0.38 μg/mL), which correlates with its highest phenolic and flavonoid contents. However, all extracts lacked antimicrobial efficacy. These findings establish distinct chemical fingerprints for sex determination and also suggest food and complementary therapeutic applications: Female for antioxidant therapy and male for antimalarial and anti‐inflammatory treatments, highlighting the importance of sexual polymorphism in C. papaya ethnopharmacology. This study is the first comprehensive comparative investigation of sex‐based differences in metabolomic profiles and associated biological activities (antioxidant, anti‐inflammatory, antimalarial, and antimicrobial) in male and female C. papaya , advancing prior research that largely examined phytochemistry or bioactivity without considering sexual polymorphism. These findings highlight the relevance of sexual polymorphism in C. papaya for sex‐specific selection in medicinal cultivation and therapeutic use.