HN equal-blunts FOXO4-DRI and navitoclax via MOMP gate
STATUS_LABEL: NEGATIVE
Claim
On a matched senescent-culture panel, humanin-class MDP (HN or HNG) blunts FOXO4-DRI senescent-cell clearance as much as it blunts navitoclax — |(%kill_drop_FOXO4-DRI) − (%kill_drop_navitoclax)| ≤ 15 percentage points, with both arms showing a pre-registered ≥20% relative kill drop vs senolytic alone; and FOXO4-DRI kill is lost or strongly reduced under Bax/Bak LOF or BAX-channel block (MOMP-execution gate).
Why it matters
P5 hoped distinct entry (FOXO4–p53 vs Bcl-2/xL/w) would spare FOXO4-DRI from HN antagonism. If execution still shares Bax/Bak MOMP, pathway-sparing fails and HN equal-blunts both senolytics. Soft-claims: discussion — equal blunt and Bax epistasis on FOXO4-DRI remain UNKNOWN; P5 is not proof of this gate.
Mechanism sketch
FOXO4-DRI enters via FOXO4–p53; navitoclax via Bcl-2/Bcl-xL/Bcl-w; HN binds Bax and blocks mitochondrial translocation / cytochrome c release. Endothelial FOXO4-DRI work frames a p53 / BCL-2 / Caspase-3 cascade — Bcl-2-family nodes can sit downstream of the FOXO4–p53 trigger without proving Bax/Bak necessity or measuring HN co-treatment. Assumption-kill: shared MOMP execution predicts comparable % blunt under HN and FOXO4-DRI dependence on Bax/Bak — stronger than “both need MOMP,” because equal blunt is a separate PREDICTION.
Prior art
- PMID 28340339 / DOI 10.1016/j.cell.2017.02.031 / PMC5556182 — FOXO4-DRI perturbs FOXO4–p53 → senescent-cell apoptosis (Baar 2017); not Bcl-xL occupancy; no HN arm.
- PMID 12732850 / DOI 10.1038/nature01627 — humanin binds Bax; blocks mitochondrial translocation / cytochrome c release (Guo 2003).
- PMID 26711051 / DOI 10.1111/acel.12445 / PMC4854923 — navitoclax senolytic via Bcl-2 / Bcl-xL / Bcl-w; cell-type restricted (Zhu 2016).
- PMID 41625068 / DOI 10.3389/fbioe.2025.1729166 / PMC12852416 — endothelial FOXO4-DRI framed via p53 / BCL-2 / Caspase-3 (2025); not Bax/Bak DKO; no HN co-treatment.
Baseline claimed
Distinct FOXO4–p53 entry protects FOXO4-DRI from HN MOMP blockade relative to navitoclax (P5 pathway-sparing hope), so equal blunt / Bax epistasis need not be tested.
Baseline measured
FOXO4–p53 entry LITERATURE (PMID 28340339). HN–Bax MOMP block LITERATURE (PMID 12732850). Navitoclax Bcl-2-family senolytic LITERATURE (PMID 26711051). Downstream BCL-2/caspase framing LITERATURE without Bax epistasis or HN (PMID 41625068). humanin∩FOXO4=0; humanin∩navitoclax∩senolytic=0; matched FOXO4-DRI±HN vs navitoclax±HN + Bax/Bak LOF UNKNOWN. Equal % blunt (|Δdrop|≤15 pp; each ≥20% relative drop) PREDICTION. P5 does not already prove this gate.
Actionable limitations
- Do not treat P5 as proving P6 — P5 listed shared MOMP as a caveat; it did not measure equal blunt or Bax epistasis.
- BCL-2 cascade language ≠ Bax requirement — 41625068 is not a Bax/Bak LOF kill of FOXO4-DRI.
- Equal blunt is stronger than shared MOMP necessity — HN potency may differ by senolytic even if both need Bax/Bak; cell-type mismatch (navitoclax-insensitive SCs) confounds H2H.
Method
propose-assay
Prediction variables
| name | kind | assay | threshold |
|---|---|---|---|
| FOXO4_DRI_p53_entry | LITERATURE | FOXO4 peptide disrupts FOXO4–p53 in senescent cells → apoptosis (Baar 2017) | FOXO4–p53 axis entry, not Bcl-xL occupancy (PMID 28340339) |
| HN_Bax_MOMP_block | LITERATURE | HN–Bax binding; blocks Bax mitochondrial translocation / cytochrome c (Guo 2003) | MOMP / cytochrome c suppression (PMID 12732850) — no KD invented |
| navitoclax_Bcl2_family_senolytic | LITERATURE | ABT-263 senolysis in restricted SC panels (Zhu 2016) | Bcl-2/Bcl-xL/Bcl-w dependent; cell-type restricted (PMID 26711051) |
| FOXO4_DRI_p53_BCL2_Caspase3_framing | LITERATURE | Senescent endothelium FOXO4-DRI via p53/BCL-2/Caspase-3 (2025) | mitochondrial Bcl-2-family nodes may sit downstream of FOXO4–p53 (PMID 41625068) — not Bax epistasis; no HN |
| matched_equal_blunt_H2H_plus_Bax_epistasis | UNKNOWN | Same senescent culture — FOXO4-DRI ± HN vs navitoclax ± HN; viability + cytochrome-c/MOMP marker; optional Bax/Bak LOF or BAX-channel block on FOXO4-DRI | dedicated equal-blunt + epistasis panel not found (soft-complete 0) — UNKNOWN |
| equal_blunt_and_MOMP_gate_margins | PREDICTION | Pre-registered matched panel; % relative kill drop under HN for each senolytic; FOXO4-DRI under Bax/Bak LOF or BAX block | both arms ≥20% relative kill drop under HN AND |
Ablate
- remove matched FOXO4-DRI ± HN vs navitoclax ± HN equal-blunt contrast: Without H2H % blunt, separate LITERATURE legs cannot show HN equal-blunts both senolytics.
- remove Bax/Bak LOF or BAX-channel-block epistasis on FOXO4-DRI: Equal blunt alone does not establish the MOMP-execution gate; pathway-sparing could fail for other reasons.
- remove P5≠proof + BCL-2-framing≠Bax-requirement discipline: Treating P5 or 41625068 cascade language as already deciding the gate would invent an epistasis/H2H result left UNKNOWN.
Refute if
On the pre-registered matched panel, HN spares FOXO4-DRI (FOXO4 relative kill drop <20% or outside the equal-blunt band while navitoclax is blunted), or FOXO4-DRI kill survives Bax/Bak LOF / BAX-channel block — pathway-sparing / MOMP-independent execution survives.
Ask a human
Lock one senescent system sensitive to both senolytics, HN exposure window, and Bax/Bak LOF vs BAX-channel-block epistasis before claiming equal blunt; do not treat P5 as proof; no dosing.
Cheap IP
kill_cost_tier=1 · time_to_refute=4w · ip_class=momp-execution-gate · vault_hold=no
Execution
execution_status=NOT_RUN · fto_status=UNKNOWN · related_prior=P5 (not proof)