Nature - USA (2020-09-24)

Article

b

48hrs

pre-treat

72hrs

ML210

Viability

cancer cells

Phospholipid nanoparticles

P

O-O

O

O NH 3 +

O

O O

O

NP1: C18:0-20:4 PE

P

O-O

O

O O O NH 3 +

O

NP3: C18(plasm)-18:1 PE

P

O-O

O

O O O NH 3 +

O

NP2: C18(plasm)-20:4 PE

O O

O

P

O-O

O

O NH 3 +

NP4: C18(plasm)-22:6 PE

P

O-O

O

O N+

O

O O

O

NP5: C18:0-20:4 PC

P

O-O

O

O O O N+

O

NP6: C18(plasm)-20:4 PC

P

O-O

O

O O O N+

O

NP7: C18(plasm)-18:1 PC

P

O-O

O

O O O N+

O

NP8: C18(plasm)-22:6 PC

P

O-O

O

O O O N+

O

NP9: C16(-O-)-20:4 PC

-2 -1.5- 1 -0.5

Vehicle

NP1: C18:0-C20:4PE

NP2: C18(plasm)-C20:4PE

NP3: C18(plasm)-C18:1PE

NP4: C18(plasm)-C22:6PE

Relative

viabilit

y

OVCAR- 8

-2 -1.5 -1 -0.5

Vehicle

NP5: C18:0-C20:4PC

NP6: C18(plasm)-C20:4PC

NP7: C18(plasm)-C18:1PC

NP8: C18(plasm)-C22:6PC

NP9: C16(-O-)-C20:4PC

Relative

viabilit

y

OVCAR-8

sgNC

-1 0

0.0

0.4

0.8

1.2

-2 -1.5 -1 -0.5

PEX3-sg1

-1.5- 1 -0.50

0.0

0.4

0.8

1.2

-2 -1.5 -1 -0.5

0.0

0.4

0.8

1.2 PEX10-sg1

-1.5 -1 -0.5 0 -1 -0.5 00 .5

0.0

0.4

0.8

1.2

-1.5 -1 -0.5 0

01

0.0

0.4

0.8

1.2

-1.5 -1 -0.5 0 -0.5 00 .5 1

0.0

0.4

0.8

1.2

-1 -0.5 00 .5

AGPS-sg2

Log 10 (M ML210) Log 10 (M RSL3) Log 10 (M ML210)Log 10 (M RSL3)

Relativ

ev

iability

Relativ

ev

iability

Relative

viability

c d

PEX3-sg1

PEX1 0 -sg1

AGPS-sg2

Relativ

ev

iability

Relativ

ev

iability

Relativ

ev

iability

sgNC

DHAP

FAR1 Fatty-alcohol

R-C-S-CoA=

O

NADPHNADP

GNPAT

1-acyl-DHAP 1-alkyl-DHAP1-O-alkyl G3P

(AGP)

AGPS PexRAP

NADPHNADP

C=O

H 2 C-O-PO 3

H 2 C-OH

C=O

H 2 C-O-PO 3

H 2 C-O-C-=R

O

C=O

H 2 C-O-PO 3

H 2 C-O-CH 2 -CH 2 -R 1

HC-OH

H 2 C-O-PO 3

H 2 C-O-CH 2 -CH 2 -R 1

PUFA-plasmalogen

PUFA-C-O-CH

O=H 2 C-O-PO 3 -X

AGPAT3

PUFA-CoA

ACSL4

PUFA

CoA

Acyl-CoA

+

R 1 -CH 2 -CH 2 -C-S-Co= A

O

Acyl-CoA

R 1 -CH 2 -CH 2 -CH 2 -OH

Fatty-acid

R-C-OH=

O Add head

group

Peroxisome Endoplasmic Reticulum

Acylation

of sn-2

H 2 C-O-CH 1 =CH 1 -R 1

TMEM189

desaturation

a

-1 -0.5 0

0.0

0.4

0.8

1.2

-1.5 -1 -0.5

-1 -0.5 0

0.0

0.4

0.8

1.2

Vehicle

NP5: C18:0-C20:4PC

NP6: C18(plasm)-C20:4PC

NP8: C18(plasm)-C22:6PC

NP9: C16(-O-)-C20:4PC

NP7: C18(plasm)-C18:1PC

-1 -0.50-0.5 00 .5

Log 10 (M ML210) Log 10 (M Erastin)Log 10 (M FIN56)

786-O

Relative

viability

-2 -1.5 -1

Log 10 (M RSL3)

e

0.0

0.4

0.8

1.2

-1 -0.500.5

Extended Data Fig. 8 | See next page for caption.