Active fractions (context-dependent): Rosmarinic acid–rich polyphenols (often dominant), plus flavones/flavonoids (luteolin/apigenin-class depending on extract). Effects vary strongly by preparation (leaf vs seed; aqueous vs ethanol; standardized vs crude).
| Rank | Pathway / Axis | Cancer / Tumor Context | Normal Tissue Context | TSF | Primary Effect | Notes / Interpretation |
|---|---|---|---|---|---|---|
| 1 | NF-κB inflammatory signaling | NF-κB ↓; COX-2, IL-6, TNF-α ↓ (reported) | Inflammation tone ↓ | R, G | Anti-inflammatory / anti-survival modulation | Most consistent mechanistic theme for perilla and rosmarinic-acid–rich fractions. |
| 2 | Nrf2 / ARE antioxidant response | Context-dependent modulation | Nrf2 ↑; HO-1 ↑; GSH systems ↑ | R, G | Redox buffering | Common polyphenol signature; tumor implications vary and may affect therapy sensitivity in some contexts. |
| 3 | ROS / redox modulation | ROS ↓ (often) or variable; pro-oxidant effects not dominant | Oxidative stress ↓ (protective) | P, R | Antioxidant-leaning redox modulation | Perilla is typically antioxidant in inflammatory/oxidative injury models; tumor cytotoxicity is usually weaker than strong pro-oxidants. |
| 4 | MAPK pathways (ERK / JNK / p38) | MAPK modulation (context-dependent) | ↔ | P, R, G | Signal reprogramming | Direction varies with extract composition and cell line; often downstream of redox/inflammation shifts. |
| 5 | PI3K → AKT (± mTOR) | PI3K/AKT ↓ (reported; model-dependent) | ↔ | R, G | Growth/survival modulation | Often secondary to NF-κB and oxidative stress pathway changes. |
| 6 | Cell-cycle arrest (G1 / G2-M) | Cell-cycle arrest ↑ (reported; modest) | ↔ | G | Cytostasis | Phenotype-level effect; strength depends on dose and extract standardization. |
| 7 | Intrinsic apoptosis (mitochondrial) | Apoptosis ↑ (reported; modest); caspases ↑ | ↔ (limited activation) | G | Conditional cytotoxicity | Usually not a “direct toxin” signature; more consistent as an anti-inflammatory/antioxidant modulator. |
| 8 | Angiogenesis signaling (VEGF) | VEGF ↓ (reported in some systems) | ↔ | G | Anti-angiogenic modulation | Evidence exists but is less consistent than NF-κB/Nrf2 effects. |
| 9 | Invasion / metastasis (MMPs / EMT) | MMP2/MMP9 ↓; migration ↓ (reported) | ↔ | G | Anti-invasive phenotype | Often downstream of NF-κB and MAPK modulation; not universal across models. |
| 10 | Extract variability / bioavailability constraint | Activity varies by part (leaf/seed), solvent, and standardization | — | — | Translation constraint | Perilla is best treated as “rosmarinic-rich polyphenol extract”; systemic exposure may not match in-vitro doses. |
Time-Scale Flag (TSF): P / R / G